DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

June 22-23, 2016 

Atlanta, Georgia 

This document has been archived for historical purposes. (7/1/2016)
Table of Contents Page

Agenda 4-5 

Acronyms 6-8 

Wednesday: June 22, 2016

Welcome and Introductions 9-17

Agency Updates





















Centers for Disease Control and Prevention (CDC)

Center for Medicare and Medicaid Services (CMS)

Department of Defense (DoD)

Department of Veteran’s Affairs (DVA)

Food and Drug Administration (FDA)

Heath Resources and Services Administration (HRSA)

Indian Health Services (I HS)

National Institutes of Health (NIH)

National Vaccine Advisory Committee (NVAC)

National Vaccine Program Office (NVPO)

17-20

Cholera Vaccine





























Introduction

Cholera Vaccine Updates

Public Comment

Recommendation Vote

20-32

Meningococcal Vaccines 

Introduction

Update: Trumenba Label

Summary of WG Discussions: Trumenba Label

Cost-Effectiveness of MenACWY in HIV-Infected Persons

GRADE for MenACWY in HIV-Infected Persons

Considerations for Use of MenACWY in HIV-Infected Persons

Proposed Recommendations

Public Comment

Recommendation Vote

VFC Vote

32-65

Evidence-Based Recommendations Work Group Update 65-66

Hepatitis Vaccine Update 66-67

Vaccine Supply 68

This document has been archived for historical purposes. (7/1/2016)


















Influenza 

Introduction

Flulaval Quadrivalent

Flucelvax Quidrivalent

Vaccine Safety Update

Vaccine Effectiveness Update

Proposed Recommendations Summary

Public Comment

Recommendations Vote

VFC Vote

69-102

Public Comment 103

Thursday: June 23, 2016









Respiratory Syncytial Virus (RSV) Vaccine—Older Adults





Introduction

Overview of RSV Vaccines

103-108

Safety of Maternal Tetanus, Diphtheria, Acellular Pertussis (Tdap)

Introduction and Enhanced Surveillance of Tdap Vaccine Safety in Pregnancy in VAERS

Maternal Pertussis Vaccination and Structural Birth Defects in Offspring

Reactogenicity and Immunogenicity of Tdap Vaccine in Pregnant Women

Pertussis Vaccines Work Group Update

108-119

Laboratory Containment of Poliovirus Type 2 119-124













Human Papillomavirus (HPV) Vaccines

Introduction

HPV Vaccine Duration of Protection

Modeling and Cost-Effectiveness 2-Dose Vaccination Schedules

HPV Vaccine Effectiveness Studies

GRADE for 2-Dose Schedules

Recommendation Options

124-150

Public Comment 150

Certification 151

Membership Roster 152-161

This document has been archived for historical purposes. (7/1/2016)
This document has been archived for historical purposes. (7/1/2016)
This document has been archived for historical purposes. (7/1/2016)
Acronyms

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ABCs Active Bacterial Core surveillance 

ACIP Advisory Committee on Immunization Practices

ACNM American College of Nurse Midwives 

AE Adverse Events

AIN Anal Intraepithelial Neoplasia 

ARI Acute Respiratory Infections 

BLA Biologics License Application 

ccIIV4 Flucelvax Quadrivalent® 

CDC Centers for Disease Control and Prevention

CDPH California Department of Public Health 

CFRs Case Fatality Ratios 

CHIP Children’s Health Insurance Program

CICP Countermeasures Injury Compensation Program 

CIN Cervical Intraepithelial Neoplasia 

CISA Project Clinical Immunization Safety Assessment Project

cLIA Competitive Luminex Immunoassay 

CMS Center for Medicare and Medicaid

COI Conflict of Interest 

COID Committee on Infectious Disease, AAP 

COPD Chronic Obstructive Pulmonary Disease 

DD Deputy Director

DFO Designated Federal Official

DNA Deoxyribonucleic Acid 

DoD Department of Defense

DSMB Data Safety Monitoring Board 

DtaP Diphtheria, Tetanus, and Pertussis 

DVA Department of Veterans Affairs

HER Electronic Health Record 

EIS Epidemic Intelligence Service 

ELISA Enzyme-Linked Immunosorbent Assay 

EMR Electronic Medical Record 

FDA Food and Drug Administration

FHA Filamentous Hemagglutinin 

FIM Fimbria 

FLU VE Influenza Vaccine Effectiveness Network

GAP Global Action Plan 

GBS Guillain-Barré Syndrome 

GCC Global Certification Commission 

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSA Gerontological Society of America 

GSK Glaxo Smith Kline 

HAIs Hospital-Associated Infections 

HCP Healthcare Personnel 

HHS (Department of) Health and Human Services

HI Hemagglutination Inhibition 

HIV Human Iimmunodeficiency Virus 

HPV Human Papillomavirus

HRSA Health Resources and Services Administration 

This document has been archived for historical purposes. (7/1/2016)
HRT Hormone Replacement Therapy 

hSBA Human Complement Serum Bactericidal Antibody 

ICD International Classification of Diseases 

IDSA Infectious Disease Society of America 

IgG Immunoglobulin G

HIS Indian Health Service 

IIV Inactivated Influenza Vaccine 

INDs Investigational New Drugs 

ISO Immunization Safety Office

JEV Japanese Encephalitis Vaccine

LAIV Live Attenuated Influenza Vaccine 

LLOQ Lower Limit of Quantitation 

LRTI Lower Respiratory Tract Illness 

MCC Meningococcal C Conjugate 

MedDRA Medical Dictionary for Regulatory Activities 

MenACWY Quadrivalent Meningococcal Conjugate Vaccine

MenB Serogroup B Meningococcal Disease

mAb Monoclonal Antibody 

MMWR Morbidity and Mortality Weekly Report

MPL 3-O-desacyl-4'-monophosphoryl lipid A

MRC (British) Medical Research Council 

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

NCC National Certification Committee 

NCIRD National Center for Immunization and Respiratory Diseases 

NFID National Foundation for Infectious Diseases 

NIAID National Institute of Allergy and Infectious Diseases 

NICHD National Institute of Child Health and Human Development 

NIEHS National Institute of Environmental Health Sciences 

NIH National Institutes of Health

NNDSS National Notifiable Diseases Surveillance System 

NNV Number Needed to Vaccine 

NPCC (Office of) National Poliovirus Containment Coordinator 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan 

NVPO National Vaccine Program Office 

OASH Office of Assistant Secretary of Health 

OPV Oral Polio Vaccine 

PACCARB President’s Advisory Council on Combating Antibiotic-Resistant Bacteria 

PAHO Pan American Health Organization 

PCR Polymerase Chain Reaction 

PCV13 Pneumococcal Conjugate Vaccine 

PhRMA Pharmaceutical Research and Manufacturers of America 

PIV Purified Inactivated Virus 

PPE Personal Protective Equipment

PRN Pertactin 

PT Pertussis Toxin 

QALYs Quality Adjusted Life Years 

RCC Regional Certification Commission 

RCT Randomized Controlled Trial

RNA Ribonucleic Acid

RSV Respiratory Syncytial Virus 

RT-PCR Reverse Transcriptase Polymerase Chain Reaction

This document has been archived for historical purposes. (7/1/2016)
SAEs Serious Adverse Events 

sBLA Supplemental Biologics License Application 

SCR Seroconversion Rate 

SCRI Self-Controlled Risk Interval 

SES Socioeconomic Status 

SGA Small for Gestational Age 

SME Subject Matter Experts 

STI Sexually Transmitted Infection 

TB Tuberculosis

Tdap Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis

THB Travelers’ Health Branch 

TIV Trivalent Influenza Vaccine

TORCH Infections Toxoplasmosis, Other, Rubella, Cytomegalovirus, and Herpes Simplex

TVC Total Vaccinated Cohort 

UCF University of Central Florida 

UK United Kingdom

US United States

V. cholera Vibrio cholerae 

VAERS Vaccine Adverse Event Reporting System

VE Vaccine Effectiveness

VFC Vaccines for Children

VICP Vaccine Injury Compensation Program 

VistA Veterans Information Systems and Technology Architecture 

VRBPAC Vaccines and Related Biological Products Advisory Committee

VSD Vaccine Safety Datalink

WG Work Group

WHO World Health Organization

WPV Wild Poliovirus 

WRAIR Walter Reed Army Institute of Research 

YF Yellow Fever

ZIP Zika in Infants and Pregnancy 

This document has been archived for historical purposes. (7/1/2016)
Call To Order & Welcome 

Nancy Bennett, MD, MS

ACIP Chair

Dr. Bennett called the June 2016 Advisory Committee on Immunization Practices (ACIP) 

meeting to order and welcomed those present. She said that they were very honored to have 

Dr. Frieden in attendance to deliver the keynote address, and invited him to give the opening 

remarks. 

Opening Remarks

Thomas Frieden, MD, MPH

Director, Centers for Disease Control and Prevention

Dr. Frieden welcomed the ACIP and thanked them for their attendance, attention, focus, and 

commitment to continuing to openly debate, discuss, and move forward immunization policy for 

the United States (US). He said that he often points to the ACIP as one of the truly great 

examples of the way this country sets health policy in a manner that combines science with an 

understanding of its impact on people. ACIP is, indeed, a model for the world and he expressed 

his appreciation for the members’ contributions and commitment. 

Recognizing that the ACIP had a full agenda and would be discussing a series of very important 

issues over the next two days, he pointed out that they also would have to address a particularly 

unusual and challenging situation with regard to influenza. Though he did not plan to discuss 

the details of what the ACIP would deliberate later in the day, he said he did want to take a step 

back to think more about actionable data. In public health, action often must be taken based on 

what is currently known. He emphasized the importance of keeping in mind that a non-decision 

is also a decision. While he was aware that ACIP had carefully assessed this for many years 

and that there are varying perspectives on it across the world, he said he wanted to challenge 

them with some of his perspectives on the issue.

He first reiterated the principles of Centers for Disease Control and Prevention’s (CDC’s) pledge 

to the American people. Dr. Walter Dowdle outlined this years ago. Dr. Frieden first saw it 20 

years ago when he was required to take ethics training with CDC. He was sitting in his home 

office in India working for CDC and the World Health Organization (WHO). He was so struck 

with the following five points that he has kept them on his desk ever since: 











Be a diligent steward of the funds entrusted to our agency

Provide an environment for intellectual and personal growth and integrity

Base all public health decisions on the highest quality scientific data that is derived openly 

and objectively

Place the benefits to society above the benefits to our institution

Treat all persons with dignity, honesty, and respect

Call To Order & Welcome, Dr. Frieden’s Opening 

Remarks, Meeting Overview, Announcements, & Introductions

This document has been archived for historical purposes. (7/1/2016)
Focusing on the principle to “base all public health decisions on the highest quality scientific 

data that is derived openly and objectively,” Dr. Frieden stressed that there was a lot packed 

into that single bullet point. He pointed out that the words “randomized controlled trial (RCT)” is 

not included in that bullet. Randomized, double-blind, placebo-controlled trials are, in fact, one 

of the great accomplishments of the 20th Century.

 

Given that his background is as a Tuberculosis (TB) Control Specialist, Dr. Frieden said that he 

must wave the flag for tuberculosis control work. In 1946, the British Medical Research Council 

(MRC) conducted the first RCT that showed unequivocally that streptomycin was effective for 

TB. In fact, streptomycin is not that good because as a single drug, one rapidly develops 

resistance. What followed from the British MRC was a remarkable, several decades long, multicountry collaboration of RCTs that optimized treatment of TB. These were truly matters of 

decades long commitment and brilliance, because the trials had recruited over a couple of years 

and followed everyone for five years. They systematically figured out how to reduce treatment 

from 12 months, to 9 months, to 6 months; how long each medication must be given; the 

different doses; and which medications were equivalent. With those treatment regimens 

developed over decades, 50 million patients have been treated over recent years as this has 

been expanded around the world.

That notwithstanding, Dr. Frieden emphasized that RCTs are a fantastic tool. However, there 

are some challenges. With regard to influenza, there is a striking disconnect between what the 

RCTs found and what other trials with other information sources found about efficacy. The 

influenza program is unique. No other vaccine is given every year. No other vaccine is 

evaluated for efficacy every year. This helps to measure the impact of public health 

interventions and determine what difference is being made in order to report, based on reliable 

model information, how many cases, hospitalizations, and deaths are prevented each year. 

Influenza is a serious and formidable challenge. Even in a “good” year, it causes millions of 

illnesses, hundreds of thousands of hospitalizations, and thousands to tens of thousands of 

deaths. The only thing that can be predicted definitely about influenza is that is unpredictable.

Dr. Frieden said that he wanted to leave the issue of influenza, which ACIP would be discussing 

in the afternoon, to speak further about RCTs. He quoted Angus Deaton, Nobel Laureate in 

Economics who said that “Randomized controlled trials cannot automatically trump other 

evidence, they do not occupy any special place in some hierarchy of evidence, nor does it make 

sense to refer to them as ‘hard’ while other methods are ‘soft.’ These rhetorical devices are just 

that; metaphor is not argument, nor does endless repetition make it so” [Deaton A. J Econ 

Literature 2010;48:424-455]. While this quote refers to the use of RCTs in development 

policies, it is equally relevant to use in medicine and science. There are definitely limitations of 

RCTs. That is not to say that RCTs are not important, not wonderful, not potentially pivotal. 

However, it is important to put them within the landscape of evidence and data used for 

decision-making.

 

Dr. Frieden said he thought it was worth outlining some of the limitations of RCTs. Some of 

these are in the implementation phase, so an RCT might be done incorrectly. However, some 

of them are inherent to the practice of RCTs. One limitation is external validity, so it may be that 

what is correct today is not correct tomorrow. It may be that there is a temporal component, or 

that what is relevant in one place is not in another. It may be that the changing epidemiology of 

disease changes the outcome, or that the program impact changes. Even if the RCT is 

meticulously done, it may lack external validity and not be generalizable to other settings. Dr. 

Frieden said he would never forget an offhand comment in an article that George Comstock 

This document has been archived for historical purposes. (7/1/2016)
wrote on TB that someone really should study the prognosis of a positive tuberculin test. Dr. 

Frieden was really confused by that remark, but was too shy to ask him for years. He finally 

asked him 20 years later, “Dr. Comstock, you did that in Alaska. In fact, it is always your studies 

that we point to when we say that there is a 5% to 10% lifetime risk of progressing from TB 

infection to TB disease. Why do you say that someone should study the prognosis of a positive 

tuberculin test?” Dr. Comstock said, “Well, because that’s what it was then. But, we don’t know 

what it is now. Maybe the force of infection was greater. Maybe there were differences in the 

genetic make-up or environmental components of the individual.” It was a remarkably 

perceptive statement from someone who had done the definitive studies and knew that they 

were not definitive.

There also are temporal changes. Treatments, exposures, and populations change. This is 

commonly observed in modern medicine where someone conducts an RCT of Intervention X 

and finds that it is no better than Intervention Y that costs a tenth as much and is much older. 

By the time it comes out they say, “Ah yes, but now we have Intervention X2 so we’re going to

use that.” There is often a situation of not having information that is relevant to the decisions 

people are making, or at least that do not appear to be relevant. In addition, there are many 

rare diseases that added up affect many people. However, there will never be enough 

participants to accrue an RCT of sufficient size.

 

Efficiency is another issue. RCTs take time and money and there are often quicker, more 

efficient ways to get an answer. There also are design and implementation limitations. These 

may be inherent or not. For example, treatment may not be standardized in the case of surgery 

or psychotherapy. Placebo effects are an interesting topic. With certain mental health 

conditions, people have such confidence in the treatment that the placebo has quite a good 

impact. That has changed dramatically over the last few decades. Randomization may be 

challenging, and controls / confounding may be issues.

RCTs generally cannot evaluate population-level interventions and impacts. In the field of TB, 

one might conduct a trial of one modality of treatment, but that may not indicate whether multidrug resistance is being risked in society as a whole. Or in the case of vaccine, there may be a 

major impact on health population or herd immunity that would not be captured in an RCT. 

Finally, there is what Dr. Frieden refers to as the “dark matter of clinical medicine.” The fact is, 

when this is considered objectively, an enormous proportion of what is done in modern medicine 

today is not based on data, and there is no realistic possibility or probability that there will be an 

RCT to evaluate it soon.

It can be said that either RCTs are the “only game in town” or that RCTs and other sources can 

be used as well when possible. A few other data sources include observational, program 

implementation and evaluation, epidemiological analyses, aggregated clinical information 

(potentially as a prelude to an RCT), and others. Program implementation and evaluation is like 

a treatment trial. A public health program can be implemented and it can be determined 

whether there is an impact. There are situations in which the aggregate information may be 

more accurate than the individual information. Aggregate information has been used to deal 

with nutritional issues, public programming issues, et cetera. In terms of aggregated clinical 

information, some of the older case series provided granular information on individual patients 

and are much more informative than some of the more recent journal articles that give 

aggregated information. With a rare condition, a case series can help to understand what 

happened and see how that might reflect on individual treatment / prognosis. Interestingly in 

terms of electronic health records (IHRs), patient registries, patient willingness to participate and 

This document has been archived for historical purposes. (7/1/2016)
share their information, there is a possibility of developing granular information across 

programs.

An example that is always raised in relation to observational or non-randomized information is 

the fiasco with the recommendation of hormone replacement therapy (HRT). There is a pretty 

strong argument that the data itself, had it been analyzed correctly, would not have led to the 

recommendation for HRT. The people who conducted that study are excellent epidemiologists. 

Everyone makes mistakes and hindsight is always 20/20. With any form of data, whether it be 

RCTs (for which limitations must be recognized) or other data sources, it is important to have 

humility because action is always being taken on imperfect data. 

On Dr. Frieden’s first day of medical school, the Dean told them, “Half of what we teach you is 

wrong, but we don’t know what half it is so you will be tested on all of it.” It is important to take a 

holistic approach to health data. That begins with having clarity about the health outcome being 

sought. Knowledge is not being sought for the purposes of seeking knowledge. Instead, 

knowledge is being sought for the purpose of improving health and addressing a specific health 

outcome. Therefore, data sources are needed that are fit to the purpose of achieving that 

health outcome. Also needed is rigor in evaluating all data sources for their strengths and 

limitations. There must be humility about conclusions regardless of the data sources, with an 

understanding that conclusions may change over time as Professor Comstock knew they might, 

or that there may be problems with the analyses, changes in modalities, and/or that viruses and 

bacteria may be evolving. The focus must be on when the data are sufficient for action. There 

always will be an argument for more research. There always will be an argument for more 

perfect data. Nevertheless, it is always important to understand that even a non-decision is a 

decision. Failure to act is a decision. The goal is to seek actionable data—data that are 

sufficient in an open, objectively derived, transparent fashion to make a recommendation and 

substantiate why.

Dr. Bennett thanked Dr. Frieden for the very inspiring and motivating presentation, which 

certainly would be taken up by ACIP’s Evidence-Based Recommendations Work Group (WG). 

She then introduced Dr. Cohn for the meeting overview, roll call, and introductions.

Overview 

Amanda Cohn, MD

Executive Secretary, ACIP / CDC

Dr. Cohn welcomed everyone to the June 2016 ACIP meeting. She indicated that the 

proceedings of this meeting would be accessible to people not in attendance via the World Wide 

Web, and welcomed those who could not attend the meeting in person. She then recognized

several others in the room who were to be present throughout the duration of the meeting to 

assist with various meeting functions: Stephanie Thomas, Natalie Greene, and Chris Caraway. 

She noted that handouts of the presentations were distributed to the ACIP members and were 

made available for others on the tables outside of the auditorium. Slides presented during this 

meeting will be posted on the ACIP website approximately two weeks after the meeting 

concludes after being made visually accessible to all viewers, including the visually disabled. 

The live webcast will be posted within four weeks following the meeting, and the meeting 

minutes will be available on the website within approximately 90 days following this meeting. 

Members of the press interested in conducting interviews with ACIP members were instructed to 

contact Ian Branam, located at the press table, for assistance in arranging interviews. 

This document has been archived for historical purposes. (7/1/2016)
The next ACIP meeting will be convened at CDC on Wednesday and Thursday, October 19-20, 

2016. Registration for all meeting attendees is required. The registration deadline for Non-US 

citizens is September 28, 2016 and for US citizens registration closes October 10, 2016. 

Registration is not required for webcast viewing. As a reminder for non-US citizens attending 

ACIP meetings, completion of several forms is required for each meeting at the time of 

registration. It is important that these forms are submitted within the required time frame. 

Stephanie Thomas, the ACIP Committee Management Specialist, will be able to help with any 

questions about the process.

Dr. Cohn then made the following announcements pertaining to Ex Officio and Liaison 

Representatives:

Ex Officio Members







Dr. Jennifer Gordon is representing the National Vaccine Program Office (NVPO)

Liaison Representatives

Dr. Corey Robertson is representing Pharmaceutical Research and Manufacturers of 

America (PhRMA)

Dr. Kimberly Thompson, Professor of Preventive Medicine and Global Health, University of 

Central Florida (UCF) College of Medicine is representing National Vaccine Advisory 

Committee (NVAC) as the Chair, replacing Dr. Walt Orenstein 

Regarding public comments, Dr. Cohn indicated that topics presented during ACIP meetings 

include open discussion with time reserved for public comment. She explained that time for 

public comment pertaining to topics on the agenda was scheduled following the end of the day’s 

sessions, and that time for public comments also would be prior to each vote by ACIP to enable 

these comments to be considered before a vote. Registration for public comments is solicited in 

advance of meetings. People who planned to make public comments were instructed to visit 

the registration table at the rear of the auditorium where Ms. Stephanie Thomas would record 

their name and provide information on the process. People making public comments were 

instructed to provide 3 pieces of information: name, organization if applicable, and any conflicts 

of interest (COI). Registration for public comment also was solicited in advance of this meeting 

through the Federal Register. Given time constraints, each comment was limited to 3 minutes. 

Participants unable to present comments during this meeting were invited to submit their 

comments in writing for inclusion in the meeting minutes.

Recommendations and immunization schedules can be downloaded from the ACIP website. 

ACIP has a policy that every three to five years each recommendation is reviewed, and then 

renewed, revised, or retired. During every meeting, an update is provided on the status of ACIP 

recommendations. There was one ACIP publication since February 2016 meeting, which is 

reflected in the following table: 

This document has been archived for historical purposes. (7/1/2016)
Applications for ACIP membership are due no later than June 30, 2016 for the 4-year term 

beginning July 1, 2018. Detailed instructions for submission of names of potential candidates to 

serve as ACIP members may be found on the ACIP web site:

E-mail: acip@cdc.gov Web homepage: www.cdc.gov/vaccines/acip/index.html

Nominations: www.cdc.gov/vaccines/acip/committee/req-nominate.html

A current CV, at least one recommendation letter from a non-federal government employee, and 

complete contact information are required. These may be submitted as e-mail attachments to 

Dr. Jean Clare Smith at jsmith2@cdc.gov

To summarize COI provisions applicable to the ACIP, as noted in the ACIP Policies and 

Procedures manual, members of the ACIP agree to forgo participation in certain activities 

related to vaccines during their tenure on the committee. For certain other interests that 

potentially enhance a member’s expertise while serving on the committee, CDC has issued 

limited COI waivers. Members who conduct vaccine clinical trials or serve on data safety 

monitoring boards (DSMBs) may present to the committee on matters related to those vaccines, 

but these members are prohibited from participating in committee votes on issues related to 

those vaccines. Regarding other vaccines of the concerned company, a member may 

participate in discussions, with the proviso that he/she abstains on all votes related to the 

vaccines of that company. It is important to note that at the beginning of each meeting, ACIP

members state any COIs. 

Announcements: Welcomes & Goodbyes

Nancy Bennett, MD, MS

ACIP Chair

Dr. Bennett shared the following announcements, welcoming individuals new to ACIP and 

wishing farewell to those who were moving on, emphasizing how sad it was to be losing several 

members. She presented Certificates of Appreciation to each departing member.

This document has been archived for historical purposes. (7/1/2016)
 Dr. Nancy Messonnier

Dr. Messonnier was named Director of the National Center for Immunization and Respiratory 

Diseases (NCIRD) in March 2016. Dr. Messonnier received her BA from the University of 

Pennsylvania and MD from the University of Chicago School of Medicine, and completed 

internal medicine residency training at the University of Pennsylvania. She joined CDC in 1995 

as an Epidemic Intelligence Service (EIS) officer in the Childhood and Respiratory Diseases 

Branch, and she served as Branch Chief of the Meningitis and Vaccine-Preventable Disease 

Branch in NCIRD from the Center’s formation in 2006 through 2012. Since 2012, Dr. 

Messonnier has held several additional leadership positions across CDC, and most recently 

served as Deputy Director of NCIRD. 

 Dr. Kathy Harriman

Dr. Harriman is Chief of the Vaccine Preventable Disease Epidemiology 

Section, Immunization Branch of the California Department of Public Health (CDPH) in 

Richmond, California. Dr. Harriman has done an outstanding job of representing public health 

on ACIP, for which ACIP is extremely grateful. Dr. Harriman believed that going to Africa to 

work on Ebola was not a good enough excuse to miss a meeting, so she decided to break her 

leg as well. She has served on the following ACIP WGs: Adult Immunization (Chair), General 

Recommendations (Chair), Meningococcal Vaccines (Member), Pertussis-Containing Vaccines 

(Member), and Hepatitis Vaccines (Member). She has helped to keep ACIP on track with her 

great public health expertise and vision.

This document has been archived for historical purposes. (7/1/2016)
 Dr. Lee Harrison

Dr. Harrison is Professor of Medicine and Epidemiology in the Infectious Diseases Epidemiology 

Research Unit at the University of Pittsburgh in Pittsburgh, Pennsylvania (PA). Dr. Harrison 

was so deeply engaged in the Zoster WG that he actually got Zoster. He has always been an 

incredible voice for everyone with inquisitive questions, calm reason, and delightful nature. He 

has served on the following ACIP Work Groups: Smallpox Vaccine (Chair), Meningococcal 

Vaccines (Member), Herpes Zoster (Member), Influenza (Member), and Meningococcal Disease 

Outbreaks (Member). 

 

 Dr. Ruth Karron

Dr. Karron is a Professor and Director of the Center for Immunization Research in the 

Department of International Health at Johns Hopkins Bloomberg School of Public Health 

Baltimore, Maryland. Clearly, Dr. Karron has magical powers. She has managed to Chair the 

Influenza WG and to convince Dr. Walter to take it over from her. Given the breadth and depth 

of the issues through which Dr. Karron has led the ACIP, this is truly striking. She has had the 

shortest tenure of any WG member on the respiratory syncytial virus (RSV) WG. Since new 

ACIP members have not yet been named, it is possible that Dr. Karron will continue to Chair 

that WG. She always asks critical questions and exhibits incredible persistence in seeking to 

acquire the most important information to help ACIP make decisions.

 Dr. Lorry Rubin

Dr. Rubin is the Director of Pediatric Infectious Diseases at the Steven and Alexandra Cohen 

Children’s Medical Center of New York of the North Shore-Long Island Jewish Health System in 

New Hyde Park, New York. He is also Professor of Pediatrics at Hofstra-North Shore LIJ 

School of Medicine in Hempstead, New York. When Dr. Rubin took over as the Chair of the 

Meningococcal WG, he was promised that it was soon to go on hiatus. It is still almost going on 

hiatus. Dr. Rubin has made incredible contributions across the board for ACIP. Though Dr. 

This document has been archived for historical purposes. (7/1/2016)
Bennett was his mentor when he joined ACIP, she said she learned everything she knows from 

him. Dr. Rubin has always been completely on point, is entirely unflappable, and his wisdom 

has helped ACIP in many ways. He has served on the following ACIP WGs: Meningococcal 

Vaccines (Chair), Yellow Fever/Japanese Encephalitis Vaccines (Chair), and Pneumococcal 

Vaccines (Member). 

Dr. Bennett thanked departing members for their service, emphasizing what a pleasure and 

honor it had been to work with them, and what sadness there was in seeing them go.

Before officially beginning the meeting, Dr. Bennett called the roll to determine whether any 

ACIP members had COIs. The following COIs were declared:







Dr. Belongia has a conflict for influenza and RSV due to receiving research support from 

Medimmune and Novovax. 

Dr. Romero has a conflict for RSV for funding non-related to vaccine trials and therapeutics.

The remainder of the ACIP members declared no conflicts.

Dr. Bennett then requested that the liaison and ex officio members introduce themselves. A list 

of Members, Ex Officio Members, and Liaisons are included in the appendixes at this end of this 

document.

Centers for Disease Control and Prevention (CDC)

Dr. Messonnier thanked everyone for the warm welcome and said that she was looking forward 

to this new role. She reported that in the June 6, 2016 Morbidity and Mortality Weekly Report

(MMWR), CDC released a VitalsignsTM on Legionnaires’ disease titled, Legionnaires’ Disease: 

Use water management programs in buildings to help prevent outbreaks. This is a new look for 

CDC at Legionnaires’ disease and the launch of a new initiative to try to be more proactive 

about the role of Legionnaires’ disease. The 2016 National Immunization Conference (NIC) will 

be convened on September 13-15, 2016 at the Hilton Hotel in downtown Atlanta. The NIC is 

one of the largest public health events sponsored by CDC, with approximately 1500 participants 

(physicians, nurses, scientists, program managers) representing all 50 states and US territories. 

It is a 3-day conference with 3 plenary sessions, 12 breakout sessions, multiple workshops, 

immunization question and answer (Q & A) sessions, exhibits, posters, and the Hilleman 

Lecture. The agenda for the event is still under development. Registration is open through 

August 22, 2016. Space is limited, so Dr. Messonnier encouraged everyone to sign up early.

Centers for Medicare and Medicaid Services (CMS)

Dr. Cohn delivered the report for CMS on behalf of Dr. Hence, who was unable to attend but 

was watching the webcast: CMS recently released the 2015 Annual Report on the Quality of 

Care for Children in Medicaid and CHIP (Children’s Health Insurance Program), and the same 

report for adults. This year for the first time, CMS developed a number of domain-specific 

reports. One of the domain-specific reports is Primary Care Access and Preventive Care in 

Medicaid and CHIP that includes information on a number of immunization quality measures. 

These reports can be found in the “Quality of Care” section of www.medicaid.gov 

Agency Updates

This document has been archived for historical purposes. (7/1/2016)
Department of Defense (DoD)

Dr. Sergienko reported that the Walter Reid Army Institute of Research (WRAIR) is working in 

conjunction with the Beth Israel Deaconess Medical Center at Harvard on two Zika vaccine 

candidates. They have been tested as single doses in mice and have been shown to be 

protective. WRAIR is moving forward with the purified inactivated virus vaccine called Zika 

purified inactivated virus (PIV) and expects to move that into human trials before the end of 

2016. Other immunization-related news is that the Accession Screening and Immunization 

Screening Program within the Defense Health Agency (DHA) Immunization Healthcare Branch 

is continuing forward. This is a program to ensure that military recruits receive the appropriate 

immunizations in adherence to accepted medical standards, and to gain clinical and economic 

advantages by delivering only the vaccines that are needed. This has been done through a 

combination of screening and serological testing, and shows that the requirements for 

immunization have been reduced for incoming recruits. There is a continuous quality 

immunization improvement process ongoing within the DHA that dispatches immunization 

healthcare specialists out to DoD facilities and immunization clinics throughout the world, 

ensuring that those installations adhere to the standards for military immunizations. The DoD 

educational training activity for the next fiscal year is ongoing, ensuring that the members of all 

of those facilities providing immunizations complete 8 hours of immunization training annually. 

For further information on all of these programs, the DHA Immunization Healthcare Branch has 

migrated from a prior website to a new website, which is www.health.mil/vaccines. This has an 

expanded portfolio on all immunization-related programs.

 

Department of Veterans Affairs (DVA)

Dr. Kim reported that DVA continues to collaborate with 5 states on the Veterans Information 

Systems and Technology Architecture (VistA) to have privately provided immunizations 

autonomously written to VA records. The plan is to add a minimum of 10 more states each 

fiscal year for the next two years. This project is also developing the capacity for inbound 

communications from the DoD for read / write to a veteran’s electronic medical record (EMR) of 

their immunizations received during military service. DVA completed a successful partnership 

with Walgreen’s for the 2015-2016 influenza season. Through this program, no cost influenza 

vaccinations for veterans were provided if they were enrolled in VA healthcare. This was a 

national program available at approximately 8000 Walgreen’s locations. Automated data 

population into the VA health record was provided through this program, as well as an update of 

the VA clinician prompts for influenza. Through this program, approximately 50,000 vaccines 

were administered to veterans at Walgreen’s, with almost all being influenza vaccines. VA 

clinical reminders, which are electronic decision support tools, were released for tetanus and 

herpes zoster immunizations for use in the VA healthcare system in May 2016.

Food and Drug Administration (FDA)

Dr. Sun reported that since the February 2016 ACIP meeting, FDA approved Flucelvax®

trivalent influenza vaccine for those 4 through 18 years of age that was previously approved for 

18 years of age and above. Flucelvax Quadrivalent® was approved for all individuals 4 years of 

age and older. Trumemba® 2-dose was approved for an alternative regimen consisting of a 0- 

and 6-month schedule. Previously, Trumenba® was approved only for a 0-, 2-, and 6-month 

schedule. On March 21, 2016, the first Fluzone® Southern Hemisphere formulation was 

approved for the US. For this year, this is based on WHO recommendations. In future years, it 

will be based on the Vaccines and Related Biological Products Advisory Committee (VRBPAC) 

This document has been archived for historical purposes. (7/1/2016)
that will probably be held twice a year now. A cholera vaccine was recently approved for 

travelers for individuals 18 through 64 years of age. In addition to these approvals, it has been 

almost a year since the Pregnancy and Lactation Labeling Rule has been in place. This is 

applicable to all drug prescribing information, and will start appearing in all vaccine labels. This 

is a way in which the FDA has tried to improve communication of safety data related to use of 

drugs and vaccines in pregnant women and women who are breastfeeding. The old pregnancy 

classification had been set aside.

Health Resources and Services Administration (HRSA)

Dr. Nair reported that the national Vaccine Immunization Compensation Program (VICP) has 

had a busy year processing claims. As of early May 2016, 637 claims have been filed for the 

current fiscal year. Thus far, 303 of these claims have been adjudicated. To date in 2016, $125 

million in awards have been paid to petitioners, and $11 million have been paid to attorneys for 

fees and costs for compensated and dismissed claims. More data about the program can be 

obtained on the HRSA website. HRSA completed development of proposed regulations to 

update the Vaccine Injury Table. The Notice for Proposed Rulemaking was issued in July 2015 

and was available for comment for 180 days, which concluded in January 2016. A hearing to 

obtain comments from the public on the proposed changes took place on January 14, 2016. 

Comments received from the public are still being reviewed in order to finalize that rule. To date 

in this fiscal year, the Countermeasures Injury Compensation Program (CICP) has 

compensated 27 claims totaling $4.5 million. 

 

Indian Health Services (IHS)

No report.

National Institutes of Health (NIH)

Dr. Gorman reported that NIH is working with four vaccine manufacturers and producers to 

enable them to develop Zika virus vaccine through Investigational New Drugs (INDs) and 

clinical trials. There is a deoxyribonucleic acid (DNA)-based vaccine, a live-attenuated vaccine, 

a genetically engineered Zika virus vaccine, and the vaccine being developed by WRAIR. On 

June 21, 2016, NIH announced that the Zika in Infants and Pregnancy (ZIP) trial would be 

ongoing. ZIP is a collaborative effort between the National Institute of Allergy and Infectious 

Diseases (NIAID), National Institute of Child Health and Human Development (NICHD), and 

National Institute of Environmental Health Sciences (NIEHS). The plan is to enroll 10,000 

pregnancies and follow the infants for infections and environmental status. An experimental 

malaria vaccine, developed by Sanaria, has been shown to provide protection for one year 

against malaria. Those who are vaccinated are followed for one year and then re-challenged in 

a challenge model. All vaccinees were protected for one year in duration. The NIAID awarded 

a large contract for the study of adjuvants, matching adjuvants with antigens and providing 

multiple adjuvants to a single adjuvant to determine whether better immune responses can be 

evoked. NIH and NIAID have a longstanding policy of not releasing promissory notes. 

However, for this particularly report, they were allowed to release a promissory note. A largescale HIV vaccine trial is being planned in South Africa. Based on the results of a previous trial 

in Southeast Asia where there seemed to be some evidence of protection, those vaccines have 

been improved or ways to increase their immune response have been changed. The trial is 

anticipated to start in November 2016 in South Africa pending the multiple regulatory approvals 

This document has been archived for historical purposes. (7/1/2016)
required between now and then. A paper was published recently pertaining to the promises and 

challenges of vaccines for hospital-associated infections (HAIs).

National Vaccine Program Office (NVPO) / NVAC

Dr. Gordon indicated that she was reporting on behalf of Dr. Gellin, who also is the Designated 

Federal Official (DFO) for the President’s Advisory Council on Combating Antibiotic-Resistant 

Bacteria (PACCARB) that was meeting at the same time as ACIP. Dr. Gelling asked Dr. 

Gordon to convey to ACIP that the Secretary asked PACCARB to provide guidance on best 

ways to incentivize the development of therapeutics, rapid diagnostics, and vaccines. In order 

to address this charge, PACCARB is in the process of establishing three WGs, including one 

that will be dedicated to understanding these issues for vaccines.

 

In terms of activities within the NVPO office, NVPO is in the process of finalizing a mid-course 

review of its 2010 National Vaccine Plan (NVP). This analysis represents a comprehensive 

stakeholder engagement to help identify and build consensus on priority areas thought to have 

the greatest potential impact for the remaining five years of the NVP. NVPO hopes to have the 

results available for distribution by the summer of 2016. The results will be used to guide the 

development of the 2016-2020 implementation plan.

As part of its effort to support adult immunization, NVPO in partnership with American Academy 

of Pediatrics (AAP), the Gerontological Society of America (GSA), and the National Foundation 

for Infectious Diseases (NFID) co-hosted the 3rd Immunization Congress: Financing Across the 

Lifespan on April 27-28, 2016 in Washington, DC. The purpose of this Congress was to identify 

the financial challenges facing different physician types in providing vaccines in their offices to 

their patient populations. The Immunization Congress is in the process of publishing the 

proceedings, which will be available soon.

 

After a highly competitive independent review, NVPO has awarded a cooperative agreement to 

Emory University in support of their research project titled, “Transforming Vaccine Hesitancy 

into Confidence—Research to Address Parents' Vaccine Decision-Making and Inform 

Development of Novel Immunization Communication Education Strategies.” This award stems 

from NVAC’s recommendations pertaining to vaccine confidence and Goal 3 in the NVP, which 

addresses vaccine communication.

 

Dr. Kimberly Thompson was recently appointed to serve as the incoming Chair of NVAC. 

NVAC convened its last meeting June 7-8, 2016 in Washington, DC. The agenda included a 

number of discussions on mechanisms to overcome economic and scientific challenges to 

vaccine research and development. There was an update on efforts to improve human 

papillomavirus (HPV) vaccinations among adolescents. Updates were presented by the NVAC 

Maternal Immunization WG and the Mid-Course Review WG. Both of these WGs plan to 

finalize their analyses for discussion during the September 2016 NVAC meeting. 

This document has been archived for historical purposes. (7/1/2016)
Advisory Committee on Immunization Practices (ACIP) Summary Report June 22-23, 2016

Introduction

Arthur Reingold, MD

University of California, Berkeley

Chair, ACIP Cholera Vaccine Work Group

Dr. Reingold reminded everyone that the Cholera Vaccine WG was formed in August 2015 with 

the relatively specific mandate of preparing for the licensure of a new cholera vaccine for use in 

the US among travelers. During the October 2015 ACIP meeting, the WG presented an 

overview of cholera background and epidemiology. During the February 2016 ACIP meeting, 

PaxVax presented VaxchoraTM clinical data and the Cholera Vaccine WG presented a Grading 

of Recommendation Assessment, Development, and Evaluation (GRADE) evaluation. 

FDA approved VaxchoraTM (CVD-103 HgR) vaccine on June 10, 2016 for prevention of cholera 

caused by serogroup O1 in adults 18 through 64 years of age traveling to cholera-affected 

areas. Vaxchora is the only FDA-approved vaccine for the prevention of cholera.

The Cholera Vaccine WG activities since February 2016 have included summarization of 

additional data on special populations (pregnant women, breastfeeding women, 

immunocompromised people, and children), shedding and transmission of vaccine strain, 

duration of protection; and development of proposed recommendations.

Dr. Reingold indicated that during this session, Dr. Karen Wong from CDC would provide a 

cholera vaccine update and proposed recommendations, followed by a vote on use of this 

vaccine.

Cholera Vaccine Update / Proposed Recommendations

Karen K. Wong, MD, MPH

Medical Officer

Division of Foodborne, Waterborne, and Environmental Diseases

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Wong reminded everyone that cholera is caused by toxigenic Vibrio cholerae O1. It causes 

watery diarrhea that may be severe and rapidly fatal without proper treatment. Cholera is 

endemic in more than 50 countries, and may also cause epidemics. Rehydration can reduce 

fatality rate to less than 1%. In the US, most cases occur among travelers to cholera-affected 

areas. Cholera is rare; however, an increase in cases in travelers from Haiti was observed after 

the epidemic began in October 2010. Safe food and water and personal hygiene measures are 

key to prevention. Populations who may be at higher risk of poor outcomes from cholera 

include travelers without ready access to rehydration therapy and medical care and travelers 

with a condition that carries increased risk of poor clinical outcomes from cholera, such as blood 

type O, pregnancy, immunocompromising conditions, cardiovascular disease, and renal 

disease. 

Cholera Vaccine

This document has been archived for historical purposes. (7/1/2016)
CVD 103-HgR is a live attenuated single-dose oral cholera vaccine that protects against 

toxigenic V. cholera infection. More than 500,000 doses of the previous formulation were 

distributed before manufacture ceased for business reasons. The vaccine was redeveloped as 

VaxchoraTM, hereafter referred to as the “new formulation” of the vaccine. Vaccine efficacy (VE) 

has been assessed by immunogenicity and protection against oral cholera challenge. 

During the February 2016 ACIP meeting, the WG presented its GRADE review and concluded 

that CVD 103-HgR vaccine is safe and effective for prevention of infection with toxigenic V. 

cholerae O1. The overall evidence type was 2. For Safety outcomes, the evidence type was 3. 

For Efficacy, the evidence type was 1. 

 

No data exist on the use of CVD 103-HgR vaccine in pregnant or breastfeeding women. 

Pregnant women are at risk of poor outcomes from cholera infection. The vaccine is not 

absorbed systemically; therefore, maternal exposure to CVD 103-HgR is not expected to result 

in exposure of the fetus or breastfed infant to the vaccine. No data exist on the use of the new 

vaccine formulation in immunocompromised populations. However, one study of the vaccine 

formulation in HIV+ adults in Mali found that vibriocidal seroconversion was slightly lower 

among HIV-positive than HIV-negative participants (58% versus 71%). No differences were 

found between vaccinated and comparison populations for any systemic adverse events (AEs). 

No data exist on the use of the new vaccine formulation in children. However, limited data exist 

on use of the older formulation. There were 10 studies that included participants 3 months to 17 

years of age. Studies were conducted in Ecuador, Chile, and Indonesia. None were in the US. 

There were no pediatric challenge studies. The vibriocidal antibody responses corresponded to 

VEs between 29% to 98%, and no association was detected between CVD 103-HgR and any 

systemic or serious adverse events (SAEs). 

Some data exist on the shedding of the new vaccine formulation strain. In two randomly 

allocated study groups combined, 11.1% of subjects shed the vaccine strain in stool at any point 

up to 7 days post-vaccination [Chen WH, Greenberg RN et al. Clin Vaccine Immunol. 

2014;21(1):66–73].

In a study of the new vaccine formulation, the vaccine strain was not isolated from stools of 28 

household contacts cultured 7 days post-vaccination. With the older formulation, the vaccine 

strain was isolated from stool in less than 1% of household contacts cultured up to 5 days postvaccine. It is important to note that both studies may miss transmission events that would be 

detected after 5 or 7 days. Seroconversion was detected in 3.7% of family contacts when 

tested at 9 or 28 days [Chen WH, Greenberg RN et al. Clin Vaccine Immunol. 2014;21(1):66–

73; and Simanjuntak CH et al. Journal Inf Dis. 1993;168:1169-76].

Duration of protection has been assessed from cholera challenge studies. For the new 

formulation, VE for protection against severe diarrhea was evaluated up to 3 months postvaccination at 79.5%. For the older formulation, VE for protection against diarrhea of any 

severity was evaluated up to 4 to 6 months post-vaccination and approached 100% [Tacket CO 

et al. J Infect Dis. 1992 Oct;166(4):837-41]. The duration of the immune response has been 

evaluated for the new formulation. Vibriocidal antibody seroconversion was detected in 90.4% 

of vaccinees up to 180 days, or 6 months, post-vaccination. No data exist on re-immunization 

with the new vaccine formulation [Chen WH, Greenberg RN et al. Clin Vaccine Immunol. 

2014;21(1):66–73; and Chen WH, Cohen MB et al. Clin Infect Dis. 2016 Jun 1;62(11):1329-35].

This document has been archived for historical purposes. (7/1/2016)
FDA announced VaxchoraTM approval on June 10, 2016 for use in adults 18 through 64 years 

old traveling to cholera-affected areas. The package insert states certain limitations of use. 

The first two concern people who may already be immune: 1) effectiveness is not established in 

persons living in cholera-affected areas; and 2) effectiveness is not established in persons with 

pre-existing immunity due to previous exposure to V. cholerae or receipt of a cholera vaccine. 

The package insert also states that the vaccine is not shown to protect against disease caused 

by non-O1 serogroups. 

The package insert states that safety and effectiveness are not established in 

immunocompromised persons. The vaccine strain may be shed in the stool of recipients for at 

least 7 days. It says to use caution when considering whether to administer VaxchoraTM to 

individuals with immunocompromised close contacts. It also mentions the establishment of a 

pregnancy exposure registry, and states that safety and effectiveness are not established in 

persons younger than 18 years of age or those 65 years of age and older. 

The WG had certain considerations for formulating the recommendation option. From the 

GRADE review, the evidence supports the safety and efficacy of the vaccine. In terms of the 

risk, cholera among travelers is rare but can be severe. Most travelers to cholera-affected 

areas are at low risk of severe infection. The WG felt that a Category A recommendation for a 

clearly defined population would be easier for clinicians to interpret and implement. The WG’s 

approach to the recommendation option was to propose a Category A recommendation for a 

defined subpopulation of travelers. This proposed recommendation would require assessment 

of the individual traveler’s risk factors and travel plans. The WG felt that the recommendation 

should be clear that vaccine is not routinely recommended for most travelers due to the low risk 

of cholera. Given that the duration of protection beyond 3 to 6 months is not known at this time, 

the WG included no formal recommendations for re-immunization in the proposed option. It is 

important to assess data on re-immunization as it becomes available and to update the 

recommendation at that time.

Dr. Wong indicated that the proposed recommendation for prevention of severe cholera among 

travelers consisted of personal protective measures and use of CVD 103-HgR vaccine. The 

vaccine portion would be a Category A recommendation. The vaccine recommendation would 

require travel to an area of active toxigenic V. cholerae O1 transmission AND increased risk of 

exposure to toxigenic V. cholerae O1 OR increased risk of poor outcome if infected. She 

presented the following text of the proposed recommendation: 

Personal Protective Measures





All travelers to cholera-affected areas should follow safe food and water precautions 

and proper sanitation and personal hygiene measures as primary prevention 

strategies against cholera infection.

Travelers who develop severe diarrhea should seek medical attention, particularly 

rehydration therapy, promptly.

Use of CVD 103-HgR Vaccine

1. Vaccination against cholera is not routinely recommended for most travelers who are 

at low risk of exposure to toxigenic V. cholerae O1. Prevention of cholera and other 

diarrheal diseases primarily depends on following safe food and water precautions 

and personal hygiene measures. 

This document has been archived for historical purposes. (7/1/2016)
2. The decision to vaccinate should be made after detailed assessment of the individual 

traveler’s risk of exposure to toxigenic V. cholerae O1 and the traveler’s risk of 

severe outcomes if infected. 

3. CVD 103-HgR vaccine is recommended for travelers to an area of active cholera 

transmission

a. who are at increased risk of toxigenic V. cholerae O1 exposure, or

b. whose individual risk factors or travel situations carry increased risk of poor 

clinical outcome if infected.

c. These populations include:















People with increased risk of exposure to toxigenic V. cholerae O1, which 

can include:

Travelers, including those visiting friends and relatives, who are 

unable to consistently follow safe food and water precautions and 

personal hygiene measures in an area of active toxigenic V. 

cholerae O1 transmission

Healthcare personnel and others who have direct contact with 

body fluids (vomitus or stool) from cholera patients

People with increased risk of poor clinical outcome if infected, which can 

include: 

Travelers who may be without rapid access to adequate 

rehydration and medical care

Travelers with a condition known to carry increased risk of poor 

clinical outcomes from cholera, such as low gastric acidity or 

blood type O

Travelers with chronic medical conditions, including but not limited 

to travelers with conditions such as cardiovascular or kidney 

disease who would tolerate dehydration poorly

There would be 2 footnotes:

1An area of active cholera transmission is defined as a province, state, or other 

administrative subdivision within a country with endemic or epidemic cholera caused by 

toxigenic V. cholerae O1 and includes areas with cholera activity within the last 1 year 

that are prone to recurrence of cholera epidemics; it does not include areas where rare 

sporadic cases have been reported. Most travelers from the United States do not visit 

areas with active cholera transmission. The vaccine is not routinely recommended for 

most travelers from the United States. 

2Long-term travelers and frequent travelers to areas of active cholera transmission may 

also be at increased risk of exposure, because the cumulative risk of exposure to unsafe 

food or water is presumed to be higher with longer duration of travel. However, data are 

limited on the duration of protection beyond 3–6 months afforded by vaccination with 

CVD 103-HgR. 

To review, the first section about personal protective measures talked about following safe food 

and water and personal hygiene precautions, and seeking medical attention promptly for severe 

diarrhea. The section about use of vaccine stated that the vaccine is not routinely 

recommended for most travelers. It recommended detailed assessment of the traveler’s risk of 

exposure and risk of severe outcomes. It stated that the vaccine is recommended for travelers 

to an area of active cholera transmission who are at increased risk of exposure, or whose risk 

This document has been archived for historical purposes. (7/1/2016)
factors or travel situations carry increased risk of a poor clinical outcome if infected. Examples 

were given of populations who meet these criteria. 

Discussion Points

Dr. Messonnier said her understanding was that the definition of “travelers” means adults, 

children were excluded, and pregnant women were not excluded.

Dr. Wong responded that it means adults for the indicated age range of 18 through 64 years of 

age. The data on pregnant women are limited or non-existent, and the WG would expect to 

elaborate on that in the recommendation. However, the recommendation does not exclude 

recommending pregnant women.

 

Dr. Belongia wondered if it was true in every country where cholera transmission is endemic 

that 99% of cases are due to O1 and a small proportion are due to O139, or if there are areas 

where O139 is more of an issue.

Dr. Wong indicated that O139 is more common in areas of Asia and Southeast Asia, but most 

cholera throughout the world is O1. 

Dr. Walter questioned whether there is any information and guidance on appropriate timing of 

vaccination prior to travel, and if there is an upper limit. 

Dr. Wong replied that the recommendation is 10 days prior to travel, and that she did not believe 

that there is an upper limit.

Dr. Moore said she appreciated the concrete definition of who should receive the vaccine, and 

wondered whether CDC would help them in implementing this by consistently updating its travel 

site with the specific areas that meet the criterion for active transmission. She could understand 

clinicians being challenged to figure out which areas meet the criterion for active transmission. 

This would be simple for the website to keep current.

This document has been archived for historical purposes. (7/1/2016)
Dr. Wong responded that the various mechanisms to report cholera epidemiology can be 

incomplete, and cholera epidemiology can change quickly. Therefore, discussion is underway 

with CDC’s Travelers’ Health Branch (THB) regarding how that website can be used to help 

clinicians assess where areas of active cholera transmission are.

Dr. Kempe suggested in the guidelines to include a linkage that will make if very easy to 

connect to this information. Another implementation-related issue is low gastric acidity. She 

asked whether that included people on chronic acid blockers, and thought some definition of 

that would be helpful.

Dr. Wong confirmed that low gastric acidity could have many causes, including medications. 

Individuals with low gastric acidity are known to be at risk for more severe outcomes. That is 

going to be a potentially large segment of the population. However, restricting the 

recommendation to areas of low transmission will confine this to a narrow population to begin 

with.

Dr. Kempe thought that if this would include people on chronic Prilosec®, this should be 

specified in the recommendation.

Dr. Belongia asked whether there was any recommendation regarding co-administration with 

oral typhoid vaccine.

Dr. Wong responded that there are no data regarding co-administration with the new vaccine 

formulation, which is stated in the package insert. There are studies with the older formulation 

that were presented during the last ACIP meeting that found no interaction when coadministered with typhoid vaccine.

Dr. Messonnier noted that the defining criteria come from defining this as only people traveling 

places where cholera is raging. Regarding the second criterion, she wondered whether any 

thought had been given to the fact that combining the proportion of those travelers who were 

either blood type O or for some reason were on acid suppressing therapy would mean that most 

people traveling to a cholera-endemic area would meet the second criterion. If so, perhaps the 

recommendation would be simpler by merely focusing on the cholera-endemic area.

Dr. Wong replied that this point was discussed extensively within the WG. Blood type O is very 

common, as are medications that cause low gastric acidity. The rationale was that defining the 

area of active cholera transmission would be the initial narrowing filter. There was discussion 

regarding the possibility of including only that point and the increased risk of exposure.

Dr. Reingold added that the WG spent a lot of timing talking about the fact that half the 

population is blood group O. In the recommendation, the attempt was to point to the fact that 

the number of people traveling to areas with substantial transmission is limited. Most travelers 

are not going to be in a situation where they are at risk of cholera or severe dehydration.

Dr. Romero asked whether there were any data on co-administration of this vaccine with 

trivalent or bivalent oral polio vaccine.

Dr. Wong responded that there were no data pertaining to the new formulation, but there are 

with regard to the older formulation that were presented during the last ACIP meeting. There 

were no interactions.

This document has been archived for historical purposes. (7/1/2016)
Recognizing that children are not included in the current language under consideration, Dr. 

Kimberlin (AAP) asked whether Dr. Wong was aware of any studies ongoing or planned in the 

pediatric population that might one day inform use of this product in people younger than 17 

years of age.

Dr. Wong requested that someone from PaxVax respond to this question.

Dr. Danzig (PaxVax) indicated that PaxVax plans to start a pediatric study in 2017 in 2 through 

18 year olds. The prior study on oral polio vaccine showed no interaction with CVD 103-HgR

and the liquid formulation of the typhoid vaccine. The oral typhoid vaccine would not be given 

co-administered with any buffer. PaxVax would be worried more about the typhoid concomitant 

administration, but there was no interaction with the bacteria.

Dr. Rubin asked whether there was any intent to offer guidance for administration of the vaccine 

to recipients who have a household or occupational exposure to immunocompromised persons. 

The FDA wording is “use with caution.” He wondered whether they should amplify on that to 

say it should or should not be used in such cases.

Dr. Wong indicated that the WG has not yet decided what should be said about people who may 

have immunocompromised household members. The package insert does indicate to “use 

caution” and there are data from the older formulation to show that transmission can occur.

Dr. Middleman (SAHM) noted that many of the young adults and adolescents she sees do not 

know their blood type. She wondered whether there were any data about whether people 

typically know their blood type and if not, whether there should be a recommendation for people 

to get a type and cross before deciding whether to get the vaccine.

Dr. Wong indicated that the WG discussed this extensively. There is no recommendation 

currently in the wording that clinicians should test blood type as part of the decision-making 

process. The WG has discussed that blood type O is very common, and people can assume 

that they are blood type O unless they know otherwise. This is probably an area for clinician 

judgment and may depend upon the person and what their other risk factors may be.

Dr. Baker expressed her appreciation for the details, data, and good questions / answers. 

However, she observed that the recommendation was very complicated. While she did not 

have a solution and knew the WG tried to be as transparent with the data as possible, it 

reminded her of a Category B recommendation in which the burden is on the physician to have 

a discussion with the patient. Even in a travel vaccine situation, there is a lot of finesse. She 

thought the recommendation was pretty complicated to be a Category A if the goal was for the 

vaccine to be used for people at risk, because it will be a large number of people.

Dr. Wong emphasized that the WG’s rationale was to make a clear and narrow 

recommendation. 

Dr. Zahn (NACCHO) asked how rare travel-associated cholera is in terms of numbers of 

reported or identified cases. He also wondered whether there was an issue for persons in need 

of malaria prophylaxis in addition to potential cholera exposure.

This document has been archived for historical purposes. (7/1/2016)
Regarding how rare is rare, Dr. Wong noted that cholera is underreported. Illness is often mild 

or moderate and self-limited, so it does not come to attention. Because of the disease duration 

and incubation period, disease may occur when people are still outside of the US. That being 

said, there may be about 100 cholera cases per year, though only a handful may be reported to 

CDC surveillance as laboratory confirmed infections. But, increases have been seen after 

certain events such as the Haiti epidemic when there were more than 40 cases reported in one 

year. There have also been some outbreaks such as the one that occurred on a plane with 

travelers returning to the US. In terms of oral prophylaxis, with the older formulation there was a 

study in which various antimalarial prophylaxis regimens were assessed. It was found that 

chloroquine may reduce the immunogenicity of the vaccine. There are no studies with the new 

formulation, but the package insert recommends against co-administration with chloroquine or 

at least spacing it out.

Dr. Mahon (SME) said she thought Dr. Baker’s point was really good. There was strong feeling 

among the WG members that a Category A recommendation would be much easier to 

implement and that they should do as much of the work of defining that as possible rather than 

deferring too much to the clinician. The sense of the WG would probably be that if there is a 

way to make the wording clearer and keep it a Category A recommendation, perhaps that would 

be more useful to the clinician.

Dr. Baker commented that CDC is such a tremendous source of what countries / locations are 

at risk for severe cholera, that information will be readily available for people to look up.

Dr. Reingold said that he recently had to advise his daughter when they were traveling through 

Southeast Asia whether to get Japanese Encephalitis Vaccine (JEV), the areas at risk, and how 

great the risk was in terms of their activities, the benefits, et cetera. He thought in some ways, 

cholera was very similar. It is very difficult to give a blanket recommendation to all travelers, 

and a lot of the burden is going to fall on physicians in travel clinics and based on good data 

from CDC and elsewhere about where active transmission is occurring. The WG could not 

come up with a way to get around that problem, so he said they would be delighted to hear 

alternative suggestions.

Regarding the surveillance issue and the fact that cholera is underreported, Dr. Thompson 

(NVAC) requested further discussion about the global surveillance quality with respect to 

identifying areas of active transmission and the challenge on the temporal side, which is that 

travelers get vaccinated before they go, but do not know what is going to occur while on travel. 

She wondered how to deal with the fact that there could be an active transmission in an area 

upon arrival that was not occurring prior to departing the US.

Dr. Wong replied that global cholera surveillance is definitely patchy. There is a WHO report, 

but reporting to that is certainly incomplete. In terms of what could happen if an outbreak 

occurs after a traveler arrives in an area, one of the primary points in the recommendation is 

that the key to prevention is following safe food and water precautions and personal hygiene 

measures.

Dr. Savoy (AAFP) pointed out that most family practice offices do not give this vaccine, but they 

may have patients who ask them whether they should go to a travel clinic to get it. With a link to 

a graphic that is easy to follow, it would not be that complicated to determine whether someone 

needs to go to a travel clinic based on where they are traveling.

This document has been archived for historical purposes. (7/1/2016)
Dr. Wong said when providing examples, they would want to offer vignettes for physicians to 

help them understand what increased risk would look like.

Dr. Kempe agreed. She was concerned that a bullet about blood type and low gastric acid 

would result in a lot of question and confusion, and said she would like to debate the downside 

of removing it.

Dr. Grogg (AOA) said that having been to Haiti during the epidemic, he was excited to have this 

vaccine available. The AOA has always recommended, if planning to travel to an area for an 

extended period where there is cholera, obtaining the vaccine in that country because the US 

did not have the vaccine. He thought more clarification was needed with regard to coadministration of Yellow Fever (YF), typhoid, malaria, et cetera. That could be in the form of a 

hyperlink. He also inquired as to the cost of the vaccine.

Dr. Wong replied that the WG would like to make the proper administration procedures as clear 

as possible for clinicians. The thought was to elaborate on a number of the issues mentioned in 

the text of the full recommendation report. Regarding the earlier comment about whether to 

remove the specific mention of blood type O and low gastric acidity, the way the 

recommendation is structured, the category of “Increase Risk of Poor Outcome” would have to 

be eliminated or change what it is called if blood type O and low gastric acidity were removed. 

She called upon PaxVax to respond to the question regarding cost.

Dr. Mark Meltz (PaxVax) indicated that the price is anticipated to be between $200 to $300 per 

single dose, which is consistent with other travel vaccines on a per course basis. 

Dr. Riley added that the other aspect of increased risk for poor outcome that the WG discussed 

extensively was the ability to be treated. If someone could be rehydrated safely, the risk of 

death would be reduced to less than 1%. It would be incumbent on the physician to find out all 

of the risk factors and determine the risk / benefits, especially for pregnancy where there are no 

data about safety.

Dr. O’Leary (PIDS) requested information regarding the magnitude of increased risk with blood 

type O and low gastric acidity.

Dr. Wong indicated that while she did not have those numbers with her, gastric acidity is 

reduced immediately and basically stays very low for people on an inhibitor. In terms of blood 

type O, the risk is for cholera gravis, which is severe cholera. Often, cholera is a mild and selflimited illness that does not even require treatment. However, cholera gravis is the rapidly 

dehydrating form of the disease with the loss of liters of diarrhea very quickly. People with 

blood type O are at increased risk for that severe, potentially life-threatening type of cholera.

Dr. O’Leary (PIDS) clarified that he was asking for the magnitude of that risk. Is it two-fold, fivefold, 20% higher?

Dr. Wong responded that she did not remember the exact numbers, but it is a substantially 

increased risk of several-fold.

This document has been archived for historical purposes. (7/1/2016)
Dr. Mahon (SME) inquired as to whether the recommendations for healthcare personnel (HCP) 

where there is discussion about having direct contact with body fluids it meant unprotected 

without personal protective equipment (PPE), or even if they have that on they should still be 

immunized.

Dr. Wong replied that the WG had not discussed that level of detail.

Dr. Romero was not sure that the physician attending to the traveler in the US would have a 

good idea of how rapid or good access they would have to medical care in the area to which 

they plan to travel. If rapid / good access to medical care is going to be used as a determining 

factor to give the vaccine or not, this needs to be further considered. He does not know what 

the access to medical care is for many of the pediatric patients he is asked to offer advice for 

when traveling to South America, Asia, or Africa.

Dr. Michael Levine (Co-Inventor of CVD103-HgR) said that regarding the question about blood 

group O, it is important to take into account that blood group O does not increase the risk of 

infection or diarrhea. It increases the chance of cholera gravis, a severe cholera that can kill 

someone if they do not get to rehydration promptly. When he teaches, he likes to use the 

example of the lowest prevalence of blood group O in the world which is in the Gangetic Delta. 

In a lovely review paper that Roger Glass wrote a few decades ago, he pointed out that in this 

home of ancestral cholera with, he thinks, the Darwinian lowest prevalence of blood group O, 

two-thirds of the cases of cholera gravis are in blood group O. In volunteers, if one gives 1 

million or 100 million organisms without buffer, one does not have positive cultures. One does 

not have diarrhea. If 1 million organisms are given with buffer, there is a 90% attack rate. 

Persons who are blood group O have a much greater propensity to develop severe cholera. 

Even an inoculum as low as 1000 organisms will give a 67% attack rate if the buffer is given. In 

terms of risk, Dr. Levine emphasized that when there are large outbreaks, particularly in the 

Western Hemisphere (as in Peru, Ecuador, and Columbia in 1991 and Haiti in 2010), the 

consequence for US travelers increases greatly and bad things can occur. It is when there is no 

access to healthcare that people are in danger. Cholera is different. Everyone knows about 

traveler’s diarrhea. Cholera is really very special. When someone is purging at a liter an hour, 

which could happen very quickly in the progression, in three hours they have lost the equivalent 

of the entire plasma volume. In five hours, they have lost the equivalent of their entire blood 

volume and they are potentially near death. This is not common, but it is like tornados. They 

are rare. Most people who live in tornado areas have not experienced it, but when it happens it 

can be very devastating. There is a nice study that Dave Taylor did in the 1990s when he was 

assigned in Peru. He cultured the American workers at the American Embassy, many of whom 

had bad traveler’s diarrhea. When the attack rate is annualized, it is like endemic disease in the 

developing world. Those folks all had easy access, but it shows how much more common 

cholera really is when one does very active surveillance, including bacteriologic culture.

Regarding the relative increased risk of people with blood group O or with low gastric acidity, Dr. 

Belongia wondered what some approximation of the risk would be among people who do not 

have those risk factors. Is the additional complexity really needed in the recommendation? 

Perhaps ACIP should state that they believe the vaccine should be acquired simply due to travel 

to an area where the risk is non-trivial, regardless of risk factors, because there is a still a risk of 

developing severe cholera. Is the risk so low for someone who is not blood group O or does not 

have low gastric acidity that they do not need to worry about it? Or if the risk is not that low, 

perhaps the complexity of these additional factors is not needed.

This document has been archived for historical purposes. (7/1/2016)
Dr. Karron thought it was important, if the recommendation was stratified, to include the 

increased risk of poor outcome in part as an educational measure for physicians. It may be that 

individuals who are on protein pump inhibitors might not want to take those if going to a choleraendemic area. It is helpful to educate the physicians about that. It may be worth doing blood 

typing. She wondered what the impact would be with removal of both narrowing categories, 

which would leave travel to an area of active transmission.

Dr. Mahon (SME) emphasized that the WG spent a lot of time discussing this, and their attempt 

was to narrow and target the recommendation as much as possible. However, as had been 

pointed out, it does not narrow it that much. She personally thought it would be reasonable to 

strike the bottom two categories and to include educational material in the recommendation 

itself if it would be easier to implement. The WG was driven very much by the travel medicine 

perspective of trying to understand exactly who would benefit most from this recommendation. 

She thought the sense of the clinicians was that this is implementable and people would not be 

vaccinated who would not benefit as much. Most people who meet the first criterion are going 

to meet one or the other of the second criteria, so it is not going to be that big of a difference.

Ms. Pellegrini said she was trying to think about this from the traveler’s perspective. It seemed 

like the recommendation was most focused on preventing the most severe cases—the 

potentially fatal cases. If she was a traveler, she would be interested in obtaining this vaccine to 

prevent herself from getting any cholera. With the recommendation as stated, they seemed to 

be saying they were okay with the mild to moderate cases. She would be happy to remove the 

qualifiers in order to prevent a greater percentage of cases, including the mild to moderate 

ones.

Dr. Moore said that one counterpoint to that perhaps was, as people are assessing travel, it is 

$200 to $300 for this vaccine. People also may be paying $200 or $300 for YF and other 

vaccines, and those are typically out-of-pocket costs. There may be value to including the 

additional criteria so that people who really should get this vaccine understand that they really 

should get it, and those who do not have higher risk factors and will have access to other 

measures can make a decision not to get the vaccine. 

Dr. Bennett requested that Dr. Mahon respond to the difference between having these two 

criteria in the recommendation versus having them in the narrative about who is at highest risk.

Dr. Mahon (SME) said she thought it was important to remember that everyone is at low risk, 

even in these categories. Only several dozen cases of travel-associated cases are seen in the 

US every year. Although it is possible that other people are getting sick while they are still 

abroad or are not being captured by the surveillance systems, the risk is still pretty low. The 

pros and cons were well-articulated, and these are the groups who would benefit the most from 

the vaccine. However, there is additional complexity in implementation that could lead to 

confusion, blood typing that could be a barrier, et cetera. Personally, she thought either way 

was reasonable and it would be possible to begin with this or start without it and try to assess 

the situation over time.

Dr. Reingold agreed that either way could work. To him the parallels were somewhat similar to 

JE because it is highly specific within a region, when traveling to an area where there are pigs 

and mosquitos.

This document has been archived for historical purposes. (7/1/2016)
Dr. Rubin suggested striking the lower right-hand part of the recommendation and having that 

as guidance, and keeping it simple in terms of being at increased risk based on itinerary. It is a 

dialogue with the patient in the travel provider’s office that occurs each day. The other risk 

factors would enter into the conversation. As Dr. Romero said, it is difficult to know a patient’s 

access to rapid rehydration in the area to which they plan to travel. This would include 

essentially everybody in the lower right-hand corner anyway.

Regarding the issue of the blood group, Dr. Sun referred to the pivotal trial for the approval of 

this vaccine, in which an assessment was made of whether a patient had blood group O or not 

and vaccine efficacy was evaluated. At the 10-day challenge versus the 3-month challenge, at 

10 days vaccine efficacy for blood group O was 84% and for non-group O was 100%. At the 3-

month challenge time point, the efficacy for the O group was 78% and for non-group O was 

83%.

Dr. Mahon (SME) said she thought if the committee wanted to strike the specifics, it would be 

best to strike both rather than just the right. The thinking was that some people are at higher 

risk of exposure and, therefore, at higher risk of illness and severe illness and some people at 

lower risk of exposure, but if they did get exposed, would be at a high risk of severe illness. 

They thought of the two as going together.

Vote: Cholera Vaccine Recommendations

Dr. Reingold motioned to approve the recommendation, striking the bottom two boxes and 

placing that information into the lengthy caveats, flow charts, and examples to inform clinicians. 

Dr. Walter seconded the motion. The motion carried unanimously with 15 affirmative votes, 0 

negative vote, and 0 abstentions. The disposition of the vote was as follows:

15 Favored: Belongia, Bennett, Ezeanolue, Harriman, Harrison, Karron, Kempe, Moore, 

Pellegrini, Romero, Reingold, Riley, Rubin, Stephens, Walter

 0 Opposed: N/A

 0 Abstained: N/A

Introduction

Lorry Rubin, MD

Chair, Meningococcal Work Group

Advisory Committee on Immunization Practices

This being his final meeting, Dr. Rubin said that he wanted to thank everyone for allowing him to 

participate in ACIP for the last four years, which he certainly enjoyed and from which he learned 

a lot.

He reminded everyone that as Dr. Sun mentioned earlier, a revised dosing schedule was 

approved for Trumenba®, Pfizer Vaccines’ MenB-FHbp vaccine. The dosing schedule was 

approved by FDA on April 14, 2016 to change the 3-dose schedule of administration to a 0.5 mL 

Meningococcal Vaccines

This document has been archived for historical purposes. (7/1/2016)
dose at 0, 1-2, and 6 months versus the previous 0, 2, and 6 months schedule, as well as the 

approval of a 2-dose schedule with administration of a 0.5 mL dose at 0 and 6 months. The 

revised schedule indicates that the choice and dosing schedule may depend upon the risk of 

exposure and the patient’s susceptibility to serogroup B meningococcal (MenB) disease.

Dr. Rubin indicated that the presentation topics for this session would include the following:























Updates to the MenB-FHbp dosing schedule, including discussion on potential policy 

options for 2-dose and 3-dose schedules, with no vote planned

Use of MenACWY vaccines in human immunodeficiency virus (HIV)-infected persons based 

on previous discussion during the February 2016 meeting, with anticipation of ACIP and 

VFC votes during this session

Focusing on the quadrivalent vaccine and HIV, two policy options were to be raised for 

discussion with ACIP during this session:

Human Immunodeficiency Virus (HIV)-infected persons aged ≥2 months should routinely 

receive MenACWY vaccine* (Category A)

OR

Human Immunodeficiency Virus (HIV)-infected persons aged ≥11 years should routinely 

receive MenACWY vaccine** (Category A)

[*Includes MenACWY-D (Menactra®), MenACWY-CRM (Menveo®), and Hib-MenCY-TT 

(MenHibrix®); **Includes MenACWY-D (Menactra®) and MenACWY-CRM (Menveo®)] 

Dr. Rubin reported that the majority of the WG members support vaccinating HIV-infected 

persons beginning at 2 months of age. The cost-effectiveness and GRADE analyses were 

based on vaccinating HIV-infected persons aged ≥2 months.

Specific topics during this session included:

Update: Trumenba® Label

Summary of WG Discussion: Trumenba® Label

Cost-effectiveness of MenACWY in HIV-Infected Persons

GRADE for MenACWY in HIV-Infected Persons

Considerations for use of MenACWY in HIV-Infected Persons

Proposed Recommendations / Vote

VFC Vote

This document has been archived for historical purposes. (7/1/2016)
Update: Trumenba® Label 

Dr. Laura York

Medical Development

Scientific and Clinical Affairs

Pfizer 

Dr. York presented an update on Trumenba®, which was licensed in October 2014 and received 

FDA approval through the accelerated approval regulations to be used in a 3-dose series of 0, 

2, and 6 months for prevention of meningococcal B disease in individuals 10 through 25 years 

of age. Recognizing that there are challenges with a 3-dose series, Pfizer continued to assess 

the data and have discussions with FDA to evaluate the potential for receiving a 2-dose 

schedule and the benefit that would be provided by that. As Dr. Rubin noted, there has now 

been a US label change. The vaccines were approved through an Accelerated Approval to 

provide access for outbreaks. Now thought is being given to the use of this vaccine in the two 

recommendations that ACIP already has in place.

As Dr. Rubin pointed out, the dosing schedule was approved by the FDA on April 14, 2016 to 

change the 3-dose schedule of administration to a 0.5 mL dose at 0, 1-2, and 6 months versus 

the previous 0, 2, and 6 months schedule, as well as the approval of a 2-dose schedule with 

administration of a 0.5 mL dose at 0 and 6 months. The revised schedule indicates that the 

choice and dosing schedule may depend upon the risk of exposure and the patient’s 

susceptibility to meningococcal serogroup B disease. Dr. York indicated that Pfizer had come to 

ACIP because providers do need guidance on how best to use these schedules.

The data that supported the 2-dose label was from a pivotal study that was included in the 

licensure, B1971012, that evaluated the safety, tolerability, and immunogenicity of 2-dose and 

3-dose schedules. These data were presented to ACIP previously prior to the initial approval. 

This study assessed two 3-dose schedules: 0, 1, 6 and 0, 2, 6 and then assessed schedules of 

0, 6 months; 0, 2 months; and 0, 4 months to evaluate how the interval may impact the immune 

response. This was a Phase II study conducted in Europe in the Czech Republic, Finland, 

Germany, and Poland in male and female adolescents 11 through 18 years of age. The primary 

endpoint was to determine the proportion of subjects achieving a human complement serum 

bactericidal antibody (hSBA) titer of at least 1:8 or over against each of the 4 primary strains 

used to measure the response that is solicited by Trumenba®. 

In terms of the immunogenicity results, this study shows the benefit of Trumenba® and the effect 

of the dosing schedule. The 0, 1 schedule is assessing the data within the 0, 1, 6 three-dose 

series to provide more information in terms of interval. With short intervals with a goal to raise 

immunity very rapidly, there is a good immune response to the four strains. These strains are 

representative of the prevalent strains in the US. They have antigens on them that differ from 

what is in the vaccine antigen, so they will display the ability of the antibody to recognize across 

a diversity of that antigen and across the diversity of meningococcal B.

 

When two doses were given in a short interval, there were robust immune responses, but they 

were less than if the interval is extended. This has been observed with other vaccines. 

Extending the interval between doses can show an improved immune response. This depends 

upon whether the goal is to illicit immunity rapidly in the case of an outbreak, or whether there is 

low risk of exposure and being able to extend that to 6 months and use two doses to have a 

high proportion of individuals who will respond to the representative strains. 

This document has been archived for historical purposes. (7/1/2016)
The 0, 2, 6 and 0, 1, 6 schedules were very comparable, which permitted moving to a schedule 

with more flexibility. Looking at the responses to each of the strains, there is similarity between 

the 0, 6 and the 3-dose series as well. Therefore, substantial benefit is provided with a 2-dose 

schedule on a 0, 6 interval in comparison to the 3-dose schedule.

The composite response is an evaluation of the number of individuals who have a response to 

all 4 strains. This offers predictive measures of what the response will be against virtually any 

meningococcal strain that will now be tested in the hSBA. It is a very good predictive value. In 

terms of 4-fold responses, there is a discernable difference between providing vaccine in a short 

interval versus the longer interval of 0, 6 and there is comparability in terms of the 0, 6 two-dose 

response and the three-dose schedules. While there are differences in this, if two doses are 

given very close together and a third dose is administered, the responses will be maximized.

 

The 0, 6 schedule does provide substantial benefit. In terms of “before vaccination,” individuals 

may have background response to a particular strain, but the requirement is to respond to all 

four strains. So vaccination provides a benefit in terms of antibody that is solicited, which will 

now recognize across that diversity. There is comparability, or at least similarity, between the 2-

dose schedule and the two 3-dose schedules. Very often, the confidence intervals overlap for 

some of the strains and may not for others, but they are very close.

This is also true in terms of the geometric mean titers (GMTs). There are differences in the 

titers achieved against the strains, but there are noticeable differences in the GMT that is 

actually achieved with 2 doses given very close together as opposed to the 0, 6 interval. Again, 

these are similar in terms of the GMT of the 2-dose compared to the 3-dose schedule.

Two isolates from one of the US outbreaks are almost virtually the same molecularly. These 

data show that there are differences in terms of strains in this in vitro assay, but the predictive 

value seen in a composite is shown in this. The predictive value of the 0, 6 schedule in terms of 

a composite is over 70% response, with a 70% to 80% response rate in terms of the 3-dose 

schedules. On a 0, 6 schedule against Strain 1, over 90% of individuals achieve a titer of 1:4, 

which is a protective value. In the 0, 2, 6 schedule the 2-dose and 3-dose schedules show 90% 

on this particular strain. The second strain is very similar molecularly, but acts differently in the 

in vitro situation. These are exploratory assays that are not very well-validated, but they do 

show the predictive value of 70% on a 0, 6 schedule and about 80% on a 3-dose schedule.

In terms of duration of protection, differences can be discerned in these data. Those data will 

be provided to the WG and ACIP before the October 2016 ACIP meeting, and certainly will be 

provided to the WG as soon as all of the cohorts within that study are collected and the testing 

done. Pfizer has followed persistence in this study for four years and then followed with a 

booster. Those data will be submitted to the WG and ACIP as well.

Regarding safety, there are no changes in the US Prescribing Information (USPI) in terms of the 

reactogenicity, et cetera. There are no changes within that document other than noting that a 

second or third dose of Trumenba® is virtually the same in terms of the safety profile. Pfizer has 

continued the evaluation of post-dose 2 and post-dose 3. Based on the cumulative safety 

summary of the 11 trials with over 15,000 subjects receiving MenB-FHbp, there is no distinction 

between the second and third dose. MenB-FHbp has demonstrated an acceptable safety 

profile. The most common local and systemic reactions were injection site pain, headache, 

fatigue, and muscle pain. Reactogenicity events were mostly mild and moderate. Median 

duration was 2 to 3 days for local reactions and 1 to 2 days for systemic reactions. There was 

This document has been archived for historical purposes. (7/1/2016)
no potentiation of reactions with subsequent doses. MenB-FHbp has demonstrated an 

acceptable safety profile when co-administered with MCV4/Tdap, dTaP-IPV, or HPV4. Similar 

proportions of newly diagnosed chronic medical conditions, autoimmune diseases, and 

neuroinflammatory conditions were reported in MenB-FHbp recipients and controls. Rates of 

SAE were similar between MenB-FHbp recipients (1.6%) and controls (1.9%).

In summary, Trumenba® (MenB-FHbp) was granted FDA approval under Accelerated Approval 

regulations in October 2014 for use in a 3-dose series (0,2,6 months) for the prevention of 

invasive meningococcal disease caused by serogroup B in individuals 10 years through 25 

years. On April 14, 2016, FDA approved a label change under the same regulations with a 

flexible 3-dose schedule (0, 1-2 months and 6 months) and a 2-dose schedule (0, 6 months). 

Both schedules have been determined to be safe and effective. ACIP guidance to providers is 

needed on the use of the FDA-approved dosing schedules for MenB-FHbp within the context of 

current vaccine recommendations for the prevention of MenB disease for use in individuals >10 

years at increased risk of disease and in adolescent and young adults.

Summary of WG Discussions: Trumenba® Label

Jessica MacNeil, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. MacNeil provided a summary of the WG’s discussions pertaining to the revised dosing 

schedule for MenB-FHbp or Trumenba®. On April 14, 2016, FDA approved updates to the 

Dosage and Administration section for MenB-FHbp. The changes allow for administration of 

both a 3-dose schedule at 0, 1-2, and 6 months, and a 2-dose schedule at 0 and 6 months. 

Additionally, the package insert now includes the following statement, “The choice and dosing 

schedule may depend on the risk of exposure and the patient’s susceptibility to meningococcal 

serogroup B disease.”

The current ACIP recommendations for the use of MenB are as follows:







Certain persons aged ≥10 years who are at increased risk for meningococcal disease 

should receive MenB vaccine (Category A)1 

A MenB vaccine series may be administered to adolescents and young adults aged 16 

through 23 years to provide short-term protection against most strains of serogroup B 

meningococcal disease (Category B)2

In the MenB Policy Notes, additional guidance is provided that states the following, which is 

consistent with the original licensing of these vaccines:

MenB vaccine should either be administered as a 3-dose series of MenB-FHbp 

(Trumenba®) or a 2-dose series of MenB-4C (Bexsero®)1,2

[

1

Folaranmi T., et al. Use of Serogroup B Meningococcal Vaccines in Persons Aged ≥10 Years at Increased Risk for Serogroup 

B Meningococcal Disease: Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR; June 12, 

2015; Vol. 64, No. 22, p 608-612; 2

MacNeil JR, et al. Use of Serogroup B Meningococcal Vaccines in Adolescents and Young 

Adults: Recommendations of the Advisory Committee on Immunization Practices, 2014. MMWR; October 23, 2015, Vol. 64, 

No. 41, p 1171-1176]. 

This document has been archived for historical purposes. (7/1/2016)
Ms. MacNeil then summarized the WG’s interpretation of data presented on the immunogenicity 

and safety data for the 2-dose schedule of MenB-FHbp at 0 and 6 months, as well as the 

proposed policy options language, and the WG’s discussion. As a reminder, several dosing 

schedules were evaluated for MenB-FHbp including two 3-dose schedules and four 2-dose 

schedules.

Based on the immunogenicity data presented by Dr. York, overall among the 2-dose schedules 

evaluated, the 0, 6 month schedule had the highest percentage of responders and GMTs and is 

most similar to a 3-dose schedule. However, the proportion of subjects demonstrating at least a 

4-fold rise in hSBA titers is lower with a 2-dose schedule at (0, 6 months) compared to either 3-

dose schedule:







2-dose schedule (0, 6 months): 73.5% (68.5-78.1)*

3-dose schedule (0, 1, 6 months): 83.1% (78.6-86.9)*

3-dose schedule (0, 2, 6 months): 81.7% (77.3-85.7)*

[*Composite response (hSBA titer ≥1:8** for all 4 strains) 1 month post-last dose; **hSBA ≥1:16 for A22 

expressing strain].

Similarly, the GMTs are lower with a 2-dose schedule at 0 and 6 months compared to either 3-

dose schedule. For some of the strains, the 95% confidence intervals do not overlap. The WG 

felt that these lower GMTs suggest not as strong of an immune response to the 2-dose MenBFHbp compared to 3 doses.

Although comparing hSBA responses following 2 doses of MenB-4C or MenB-FHbp is 

somewhat like comparing apples to oranges because of differences in the strains tested and the 

study population, the WG did feel that these were important data to consider as part of this 

discussion.

The following graphic shows the composite hSBA response one month following two doses of 

MenB-4C on the left and MenB-FHbp on the right, with varying intervals between those two 

doses: 

This document has been archived for historical purposes. (7/1/2016)
In general, the responses following 2 doses of MenB-FHbp are similar and are slightly lower 

than the response following 2 doses of MenB-4C.

Preliminary antibody persistence data following the 2-dose schedule of MenB-FHbp was 

recently shared with the WG, and it is anticipated that more complete antibody persistence data 

may be available to be shared with the full ACIP in October 2016.

As presented to ACIP previously, the MenB vaccines are generally more reactogenic than other 

vaccines given during adolescence. The most common AE reported is pain at the injection site. 

Overall, the safety and tolerability profiles are similar for the 2-dose and 3-dose schedules of 

MenB-FHbp.

After reviewing these data, the WG has discussed several different policy options. For persons 

at increased risk and for use during outbreaks a preference for a 3-dose schedule of MenBFHbp would be stated. For healthy adolescents, there are two options: 1) a 2-dose schedule of 

MenB-FHbp at 0 and 6 months or the 3-dose schedule could be given; or 2) a preference for a 

3-dose schedule of MenB-FHbp could be stated and guidance could be provided that if 

someone receives their second dose of MenB-FHbp 6 months after the first dose, no additional 

doses are needed.

Based on the WG’s discussion, there was strong consensus among WG members to express a 

preference for a 3-dose schedule for persons at increased risk, including outbreaks, in order to 

provide early protection and maximize the immune response. There also was a strong 

preference for a 3-dose schedule for healthy adolescents. For people who want to maximize 

protection, 3 doses are preferred. Both the 2- and 3-dose schedules take 6 months to 

complete. Guidance could be provided that if someone receives their second dose of MenBFHbp 6 months after the first dose, no additional doses are needed.

Additional data are anticipated to be available for ACIP to consider in October 2016, which 

include the following:







Results of antibody persistence following a 2-dose (0, 6 month) schedule

Results from an independent evaluation of hSBA data for MenB-FHbp and MenB-4C against 

several US outbreak strains, which clearly show the benefits of a third dose of MenB-FHbp 

Results of a study on the impact of MenB-FHbp on carriage among US college students

In addition to hearing ACIP’s feedback about the data presented, during the discussion the WG 

also hoped to obtain: 1) feedback on whether ACIP is in agreement with the WG’s proposal to 

express a preference for the 3-dose schedule of MenB-FHbp in persons at increased risk, 

including outbreaks and healthy adolescents; and 2) whether there are additional data beyond 

data proposed for October 2016 that ACIP would like to see.

Discussion Points

Dr. Kempe asked whether there were plans to compare the cost-benefit for 2 versus 3 doses in 

healthy adolescents in terms of evaluating the additional potential benefit of the third dose.

Ms. MacNeil indicated that the WG had not planned to perform an analysis comparing the costbenefit for 2 versus 3 doses, but could discuss this.

This document has been archived for historical purposes. (7/1/2016)
Regarding the preference of the 3-dose schedule for healthy adolescents, Dr. Karron asked 

whether there is clear evidence that 3 doses maximizes protection relative to 2 doses.

Ms. MacNeil indicated that based on the immunogenicity data, there is a slight increase with 3 

doses versus 2.

Dr. Karron asked for clarification about whether the confidence intervals overlap when the doses 

are given at 0 and 6 months, and Ms. MacNeil confirmed that they do. Therefore, Dr. Karron 

thought ACIP should consider this as an issue as well as with regard to the wording of the 

recommendation. She did not know that they had data to suggest that 3 doses maximizes 

protection over 2 doses in a healthy adolescent population.

Dr. Reingold asked who would be left such that there would not be a preference for a 3-dose 

schedule if those at increased risk in outbreaks and healthy adolescents were subtracted out.

Ms. MacNeil replied that there would be a preference for everyone for whom there is a current 

recommendation.

Dr. Grogg (AOA) asked Dr. York for clarification regarding whether the subfamilies that are 

tested and give a robust response were the same strains in the vaccine. If so, this would 

indicate to him that there is cross-protection.

Dr. York responded that this was correct. Strains were selected that would have antigens 

expressed that differed from the vaccine components. The assumption is that there is crossprotection. Instead of trying to match it to show a response to a vaccine, Pfizer approached this 

to show the breadth of the ability of the antibody to recognize across a diversity of US strains.

Dr. Stephens said it would be helpful to know about predicted strain coverage across US 

strains, for example. He requested that Dr. York elaborate on those data.

Dr. York indicated that Pfizer has performed exploratory analyses on outbreak strains in the US 

and France, which she presented during the last ACIP meeting. With the 2-dose and 3-dose, it 

is really quite predictive. Some strains are more difficult to develop in these assays, but the 

composite provides an idea of the minimum. It varies depending on the strain, regardless of the 

FHbp antigen.

Cost-Effectiveness of Meningococcal Vaccination in HIV-Infected People in the US

Ismael Ortega-Sanchez, PhD

Senior Health Economist

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Ortega-Sanchez indicated that following the ACIP Guidance for Health Economics Studies, 

this study was reviewed by CDC. The review provided important observations that were 

addressed for this presentation, with explicit responses to some comments included at the end.

The purpose of this study was to analyze the effectiveness and cost-effectiveness of a potential 

vaccination program for persons living with HIV against meningococcal disease with a primary 

series of MenACWY followed by lifelong 1-dose boosters every 5 years. For people less than 7 

This document has been archived for historical purposes. (7/1/2016)
years of age, the booster dose would be every 3 years. The societal perspective was used for 

this analysis.

For this study, the investigators resorted to the previously constructed decision tree model to 

compare the strategies, with vaccination and without vaccination for each cohort:

For the complete number of cases as well as the number of deaths and survivors with sequelae, 

the model includes nodes that describe infection and non-infection and specific outcomes. A 

similar model was presented to this committee in the past. To deal with key uncertainties, the 

decision tree model also is designed with a Monte Carlo simulation analysis. This simulation 

allows for calculation of not only the most likely or base case estimate for health benefits and 

costs, but also the ranges around these estimates. For that, an age-specific HIV+ population is 

included that is comprised of approximately 934,000 HIV+ subjects distributed by age. Each 

age group is followed until 70 years of age, which is the timeframe. Benefits of vaccination are 

over the age-specific life expectancy, for which a discount rate of 3% is used for both costs and 

benefits.

Once the core of the model was set, the best available data were used, including the following:









Age-specific HIV+ population (2013)

Age- year- and Mening ACWY serogroup-specific incidence rates (2005-2014)

Age- and Mening ACWY serogroup-specific case fatality ratios (2005-2014)

Proportion of survivors with sequelae by condition after meningococcal disease

The model uses data for people living with HIV by age from the HIV Surveillance Report, 2014. 

It is quite important for modeling vaccine to determine the proportion of people living with HIV in 

Stage 3. For the lower bound, the data used was the proportion of new Stage 3 diagnoses for 

2013, while the upper bound was based on the Revised Surveillance Case Definition for HIV 

Infection, which is based on CD4 counts. The assumption was made that the average life 

This document has been archived for historical purposes. (7/1/2016)
expectancy of people living with HIV is similar to the general population for the upper bound, 

and about a 7-year reduction in people living with HIV in the lower bound.

There are two important characteristics regarding the incidence data of people living with HIV 

who are in the model: 1) the proportion of cases who are HIV+ are from Active Bacterial Core 

surveillance (ABCs) and incidence data from the National Notifiable Diseases Surveillance 

System (NNDSS), with additional serogroup data from ABCs and state health departments; and 

2) incidence data for 0 to 19 years is from NNDSS, with additional serogroups data from ABCs 

and state health departments for the general population regardless of HIV status.

Strategies of vaccination with MenACWY in the US are as follows:















≥2 years of age:

Primary series: 0, 2 months

Boosters: life-long boosters required

Current booster recommendations: 3 years if age <7 years at previous dose and 5 years if 

age ≥7 years at previous dose

<1 year of age:

Primary series: 2, 4, 6, 12 months

Boosters: same as above

1-2 years of age:

Primary series: 0, 3 months

Boosters: same as above

One key component is the initial VE based on CD4 counts. The specific efficacy used in the 

model was:

High CD4 count with 2 doses series: 75% (37% to 91%)

Low CD4 count with 2 doses series: 37% (24% to 60%)

The initial efficacy was based on combined efficacy from the Open-Label Trial of Safety and 

Immunogenicity of Meningococcal Groups A, C, Y, and W.

In the same way, the coverage rate was assumed for primary series and any booster dose as 

follows: 

Primary series (2 or 3 doses): 65% (40% to 80%)

Booster dose (every 5 years): 45% (30% to 65%)

Rates of coverage for the primary series and booster assumptions were based on various 

sources.

The second component of VE regards how initial protection wanes over time. For preliminary 

assumptions, linear and exponential decay curves were fitted to antibody waning through 

available SBA data. Such waning was adjusted for low and high CD4 counts and for the first 

and second dose in the series. A key assumption in the model is that the efficacy of each and 

any booster dose is assumed to follow a similar waning protection pattern.

This document has been archived for historical purposes. (7/1/2016)
Therefore in the model, the meningococcal disease incidence and vaccination were modeled 

using the following expression:

MDIvacc = MDIno vacc * [1-(Vcov * IntVEff * Residualt )]

Where:

• 

• 

• 

• 

• 

MDIvacc = Meningococcal disease incidence under vaccination

MDIno vacc = Meningococcal disease incidence without vaccination

Vcov = Vaccination coverage

Int VEff = Initial vaccine efficacy

Residualt = Residual vaccine efficacy (0-100%) t years after vaccination t = 0,...,T

No indirect effects were introduced into the model, because it is considered a vaccination 

primed to a target population. Once the disease incidence is calculated with vaccination and 

with no vaccination, the health outcomes were estimated. First, mortality was estimated using 

the case fatality ratios (CFRs) specific for serogroups ACWY in HIV+ persons based on NNDSS 

meningococcal cases with and without reduction as observed in ABCs data for HIV+ cases for 

the US, 2005-2014. Second, the proportion of survivor cases with sequelae was calculated by 

type of condition. The following table shows the rates of sequelae by type of condition, with 

point values and ranges that were used in previous analyses:

Skin Scarring 7.6 (0 - 19)

Single Amputation 1.9 (0.5 - 10)

Multiple Amputations 1.2 (0.02 - 6)

Hearing Loss* 8.8 (2 - 20)

Significant Long-Term Neurologic Disability** 2.1 (0.02 - 11)

*Edwards et al. Complications and sequelae of meningococcal infections in children. J Pediatrics 1981; 99:540-5 

**Baraff et al. Outcomes of Bacterial meningitis in children: a meta-analysis PIDJ 1993;12:389-94 

Once outcomes of meningococcal disease were defined, the quality-of-life lost to each of these 

complications must be assessed. However, the baseline 1Health Utility Index must be adjusted 

to take into account the underlying HIV infection and the perceived quality-of-life among people 

living with HIV. That is done before any meningococcal infection and the impact of the specific 

complications. Therefore, the baseline scores for people living with HIV are adjusted using the 

marginal effects from HIV, which are taken from a study on the 2health-related quality-of-life of 

people living with HIV versus the general population. The adjustments are done by age, 

sexuality, CD4 counts, and date of diagnosis [1Health Utilities Index, Mark 3, (HUI-3) combined 

for males and females. Sources: (1) http://www.healthutilities.com/HUINormsKeyTable.htm (2) 

This document has been archived for historical purposes. (7/1/2016)
http://www.chepa.org/Files/Working%20Papers/01-02.pdf; and 2Adjusted for Age, Sexuality, 

CD4 counts (AIDS) and Date of diagnosis. Source: Miners et al. "Health-related quality-of-life of 

people with HIV in the era of combination antiretroviral treatment: a cross-sectional comparison 

with the general population. The Lancet V1, (1), October 2014, e32–e40]:

AGE

(in years)

Health Utility Index 

General Population1

Marginal Effect in 

Utility Score from 

HIV2

Health Utility Index 

People Living with 

HIV

<24 92.2% -11.0% 81.2%

25-34 92.2% -11.0% 81.2%

35-44 92.3% -13.0% 79.3%

45-54 91.5% -13.0% 78.5%

55-64 88.1% -14.0% 74.1%

65-74 86.4% -14.0% 72.4%

75-84 83.9% -14.0% 69.9%

85+ 78.5% -14.0% 64.5%

Once the baseline for quality-of-life is adjusted for people living with HIV, the related quality-oflife scores are applied for specific meningococcal complications as shown in the following table, 

which is done to estimate the quality adjusted life years (QALYs) lost to meningococcal to 

disease or the QALYs saved with vaccination:

The following chart is intended to illustrate what goes into cost calculations for the various 

outcomes of cases of meningococcal disease in this model:

This document has been archived for historical purposes. (7/1/2016)
Finally, the vaccine costs were based on the March 2016 public and private sector prices of 

Menveo or Menactra®. The cost of the vaccination program includes the cost of the dose, the 

cost of administration, and the proportion of waste due to vaccination problems. Note that the 

rates of AEs included in the vaccination program were taken from the United Kingdom (UK) 

experience with meningococcal C conjugate (MCC) vaccine.

Regarding the preliminary results, the baseline per age group of HIV+ persons with no 

vaccination are shown in this table:

Note that because of the small numbers of people living with HIV in some age groups and 

because of the low incidence and mortality rates of meningococcal disease, the number of 

cases, deaths, and QALYs lost are very small. The age groups with the highest meningococcal 

disease burden are observed from 20 through 24 years of age and from 50 through 59 years of 

age.

This document has been archived for historical purposes. (7/1/2016)
Once a vaccination program is implemented in the model, the total number of meningococcal 

cases and deaths averted in people living with HIV are shown below:

These estimated distributions are from Monte Carlo simulation. Based on this simulation, the 

mean number of cases averted was 122 and the mean number of deaths averted was 23.

Once the vaccination program is implemented in the model, the total cost of QALYs saved in 

people living with HIV vaccinated against MenACWY are shown below:

The average number of QALYs saved is 385 and the cost is about $730,000 per QALY. 

However, it is important to look more closely at which specific age groups of people living with 

HIV have high impact from vaccination. The following table shows the base case by age group, 

the number of cases, deaths prevented, and number of QALYs saved:

This document has been archived for historical purposes. (7/1/2016)
As expected, the age groups where the highest vaccine impacts are observed are among those 

20 through 24 years of age to 50 through 59 years of age.

To get an idea of the costs, the following graphic shows the base case for cost of disease with 

vaccination and the cost of vaccination program for each age group. Also shown are the base 

case net costs by age group:

The following graphic presents the cost-effectiveness analysis among all age groups. The 

diamonds are the mean values from the Monte Carlo Simulation, and the 5th and 95th percentiles 

are the ranges in bars. Note the U-shape when age is changing:

This document has been archived for historical purposes. (7/1/2016)
In order to see the incremental cost-effectiveness of meningococcal vaccination by age group, 

economists use the following type of graph that shows the cost per QALY in the Y-axis and the 

QALYs saved on the X-axis and draws a line to the one that has the lowest slope, which is 

considered to be the most cost-effective intervention:

Based on this graph, the age groups that provide the most QALYs are those that range from 20 

through 24 to 40 through 50 to 54 years of age. The people on the left-hand side are providing 

less QALYs saved, which is due to the small numbers in those age groups living with HIV and 

the lowest incidence and mortality rates.

This document has been archived for historical purposes. (7/1/2016)
When specific scenarios are selected and some of the variables are changed in the base case 

assumptions, changes can be seen in those assumptions and the QALYs and costs per QALY 

saved as shown in the following table:

The following table provides a base case comparison for cost per QALY among some 

vaccination programs recommended and some not recommended: 

There are a number of limitations in the analysis. Data on incidence and mortality among 

people with HIV are limited. Data on initial VE are from serology and immunogenicity. Data on 

duration of VE also is limited, though strong assumptions have been used to try to determine 

the best estimates.

This document has been archived for historical purposes. (7/1/2016)
49 

As mentioned earlier, following the ACIP Guidance for Health Economics Studies, there were a 

number of comments / suggestions made by the reviewers inside the CDC. The comments 

provided for Parts 1 and II, along with the responses from the investigators, were as follows:

Part I

Comment 1. “[C]oncerns about the numbers presented for the number of people living 

with AIDS:

Using the “Revised Surveillance Case Definition for HIV Infection - United 

States, 2014” we re-estimated the percentage range of people living with HIV 

in stage 3, along with a scenario analysis

Comment 2. The reduction in cases of disease as a result of vaccination does not seem 

to line up with the assumptions about vaccine efficacy, vaccine coverage, and waning of 

protection: 

We reviewed the model calculations for formulas and parameter values and 

health outcomes and costs were re-estimated

Part II

In Comments 3 to 9. Reviewer provided “minor” or “editorial” comments which were 

addressed in these slides and in the technical report

In conclusion, routine vaccination of people living with HIV with a primary series plus periodic 

boosters against Meningococcal ACWY disease is relatively costly. Disease cases, deaths 

(both with relatively low numbers), and vaccine costs of lifelong booster doses drive the 

analyses. Although costly, additional cases could be prevented by all vaccination strategies.

Discussion Points

Dr. Thompson (NVAC) asked whether less waning than the base case was evaluated, and 

related to that whether people who wane, wane back to the same level as fully susceptible 

individuals with respect to their risks for the specific outcomes or sequelae.

Dr. Ortega–Sanchez replied that the assumptions about waning were taken from the open-label 

immunization data, most of which were for children and adolescents that were extrapolated to 

the other age groups. For the sensitivity analysis, consideration was given to what would 

happen if the waning was faster, which was following the 5th percentile. The number of QALYs 

saved and the cost per QALY changed in the direction expected. Only 296 QALYs saved and a 

cost of $901,000 per QALY. The assumptions can be changed. In fact, he has been 

performing a number of experiments with that assumption because it seems to be the one that 

drives the analysis. Again, the data are limited and the ranges provided to each one of the 

mean points are supposed to be included in some of the uncertainty that was observed in the 

variables.

Dr. Reingold asked for an approximate number needed to vaccine (NNV) to prevent one case, 

and a reasonable number of assumptions about duration of protection and if there is full 

coverage, approximately how many cases and deaths would be prevented per year in the US.

Dr. Ortega–Sanchez responded that the model is allowing him to calculate the NNV and he has 

been assessing those estimates. Some of the age groups were so small that more people than 

This document has been archived for historical purposes. (7/1/2016)
in the age groups would need to be vaccinated in order to prevent one case in those age 

groups. For example, for those less than 13 years of age, he had to determine how to distribute 

all 2415 cases among all of those 12 years, and then try to include the incidence data to come 

up with cases. Not all 2415 would be vaccinated, because there are assumptions about 

coverage. The NNV to prevent one case among one of these age groups was higher than the 

2415, for example. It is basically the same for some of the other age groups. He can provide 

those data, and some data were provided in the extra slides to support the assumptions. He 

was not able to provide the estimate year-by-year of cases and deaths averted, because this 

cohort was followed for 70 years. In 70 years, about 122 cases would be prevented. That is 

approximately 45% of the total number of cases observed in the same period. If that is 

distributed by year, the numbers are very small.

Dr. Messonnier pointed out that this information was going to be discussed in the upcoming 

GRADE presentation.

While Dr. Whitely Williams (NMA) thought this was an excellent effort to try to answer the 

question, the modeling did not take into account the social background and environment of this 

population. For example, there was an outbreak of meningococcal meningitis in Chicago. Of 

the 7 cases, 6 were HIV-infected and 1 was not. She said she made this comment because 

eventually, had the investigation not used the infrastructure that was in place to support persons 

with HIV infection, it would have been difficult to understand what was occurring with that 

outbreak and it potentially could have spread to the general population. Obviously, it was good 

that there was a social support and environment existed in order to be able to recognize and 

control that outbreak, she though they needed to be very careful about the modeling to come to 

a conclusion that this would be very expensive in terms of the use of this vaccine in this 

particular population.

GRADE for MenACWY Vaccines for HIV-Infected Persons

Monica Patton, MD

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Patton presented the WG’s GRADE process for the MenACWY vaccines for HIV-infected 

persons. She reviewed the study question and presented a modified assessment of disease 

burden data, an assessment of evidence for outcomes, and the WGs determination of overall 

evidence type. The first step in the GRADE process is to formulate the study question. The 

overall question for this analysis was, “Should MenACWY vaccines be administered routinely to 

all HIV-infected persons aged 2 months and older for prevention of meningococcal disease?”

There are three conjugate vaccines licensed for use in the US. Menactra® covers serogroups 

A, C, W, and Y and is licensed for use among persons aged 9 months to 55 years. Menveo®

covers serogroups A, C, W, and Y and is licensed for use among persons aged 2 months to 55 

years. Menhibrix® covers serogroups C, Y, and Haemophilus influenzae type b and is licensed 

for children aged 6 weeks to 18 months.

This document has been archived for historical purposes. (7/1/2016)
The following table summarizes the outcomes that were chosen for the question:

Assessment Outcome

Modified assessment of 

disease burden data

Cases/Incidence

Mortality

Quality of evidence assessed 

using standard GRADE 

approach

Short-term immunogenicity against serogroups 

A, C, W, Y

 -4 weeks after 1st dose (week 4)

-4 weeks after 2nd dose (week 28)

Persistence in immunogenicity against 

serogroups A, C, W, Y

-48 weeks after 2nd dose (week 72)

Serious adverse events

The first 2 outcomes were not assessed using GRADE since they are surveillance data. A 

modified assessment was made of these data. The last 3 outcomes were assessed using 

GRADE. Dr. Patton first discussed the modified assessment of disease burden data and then 

described the GRADE process for the outcomes listed.

Because low disease incidence is an important consideration for meningococcal infections 

among HIV-infected persons, the WG wanted first to evaluate the quality of the meningococcal 

disease burden data. However, because these are surveillance data and no intervention was 

tested, they could not evaluate them using the GRADE format. Instead, the disease burden 

data were assessed for representativeness and completeness.

US meningococcal incidence data come from two sources: ABCs and NNDSS. ABCs is an 

active laboratory and population-based surveillance system that collects data on cases of 

meningococcal disease in 10 sites that cover 43 million persons, or approximately 14% of the 

US population. Because case reports include chart review, HIV status of cases should be 

included in ABCs data. NNDSS is a passive surveillance system. All states and territories 

report data for nationally notifiable diseases to NNDSS. However, NNDSS does not contain 

HIV status. Because cases identified in ABCs are also reportable to NNDSS, these are not 

independent surveillance systems.

Between 1995 and 2014, a total of 62 meningococcal cases were reported among HIV-infected 

persons in ABCs, which is approximately 2% of all cases reported to ABCs during that time 

period. Here we see the cases among HIV-infected person by age group in years and by 

serogroup:

This document has been archived for historical purposes. (7/1/2016)
Approximately 80% of cases occurred among HIV-infected persons aged 20 through 49 years 

and approximately 70% of cases were serogroup C, W, or Y.

A chart review of ABCs data from 2000-2008 was performed in order to determine the incidence 

of meningococcal disease among HIV-infected persons in the US. A total of 33 cases from HIVinfected persons were included in the chart review. However, because the population of HIVinfected persons in ABCs was unknown due to variable HIV reporting requirements by state 

during that time period, incidence calculations were limited to the 17 meningococcal cases 

among HIV-infected persons in ABCs who met the CDC AIDS surveillance case definition 

because name-based AIDS cases were reported in all states during that time. The analysis 

found an incidence of 3.5 per 100,000 person years among cases who met CDC AIDS criteria 

compared to 0.3 per 100,000 person years among all other cases, with a resulting relative risk 

of 12.9 [Harris CM et al. Meningococcal Disease in Patients with HIV Infection-A Review of 

Cases Reported Through Active Surveillance in the United States, 2000-2008. Manuscript 

Under Preparation].

However, there are a few things to keep in mind with respect to the quality of data regarding 

meningococcal disease among HIV-infected persons in ABCs. This is a map of ABC sites in 

2014:

This document has been archived for historical purposes. (7/1/2016)
However, the ABCs catchment area during 2000 to 2008 used to calculate the incidence of 

meningococcal disease among HIV-infected persons is a somewhat different picture. For 

example, Colorado joined ABCs in 2001 and New Mexico joined in 2004. Additionally, cases 

were excluded from Maryland in 2000 and New York during the entire study period because of 

local health information disclosure policies pertaining to HIV infection.

 

When the proportion of the HIV-infected US population is calculated in the ABCs catchment 

area by year, the ABCs catchment area represented from 9% to 17% of the HIV-infected US 

population aged 14 years and older, and the proportion of HIV-infected US children aged 0 

through 13 years represented by the ABCs catchment area was even lower, ranging from 6% to 

9.8% per year.

 

Additionally, when considering the quality of surveillance data to identify meningococcal disease 

among HIV-infected persons, it is important to recognize that HIV testing rates among adults 

and adolescents are suboptimal. For example, the proportion of adults who had ever been 

tested for HIV increased from 37% in 2000 to 45% in 2008, and only 12% to 13% of adolescents 

were ever tested for HIV in 2005 and 2007.

 

However, despite the limitations of the case / incidence data of meningococcal disease among 

HIV-infected persons in ABCs, the available estimates are supported by a number of other 

studies that have investigated the incidence of meningococcal disease in HIV-infected persons 

as shown in the following table:

This document has been archived for historical purposes. (7/1/2016)
:

Most of these studies were presented to ACIP during the last meeting. It is important to 

recognize that these studies occurred over a 4-decade time period when many advances in HIV 

testing, care, and treatment occurred, resulting in studies that span variable HIV testing rates, 

variable availability of antiretroviral therapy, and variable severity of disease. However, the 

available studies show a 5- to 14-fold increased rate and a 5- to 24-fold increased risk of 

meningococcal disease among HIV-infected persons compared to HIV-uninfected persons that, 

taken together, suggest a possible benefit of MenACWY vaccination for persons with HIV 

infection.

In terms of mortality among HIV-infected persons with meningococcal disease, case-fatality 

ratios were analyzed for HIV-infected and HIV-uninfected persons with meningococcal disease 

in ABCs in the chart review between 2000 and 2008 and overall between 1995 and 2014. 

There was no statistically significant difference in case-fatality ratios between HIV-infected and 

HIV-uninfected persons in either analysis, with a case-fatality of 13% among HIV-infected 

persons compared to 11% of HIV-uninfected persons during 2000 to 2008, and case-fatality 

ratio of 16% among HIV-infected persons compared to 11% in HIV uninfected persons overall 

from 1995 to 2014.

Other studies that have assessed case-fatality ratios among HIV-infected and HIV-uninfected 

persons with meningococcal disease have demonstrated mixed results. While the Australian 

and South African studies demonstrated higher mortality among HIV-infected persons with 

meningococcal disease compared to HIV-uninfected persons, the studies from New York and 

England demonstrated higher mortality among HIV-uninfected persons. There are a number of 

reasons mortality may be lower among HIV-infected persons in the more recent studies, 

including the fact that many HIV-infected persons may be engaged in healthcare services where 

more rapid assessment of symptoms and referral to appropriate medical care may occur. 

Additionally, HIV-infected persons may receive antibiotic prophylaxis or be on antiretroviral 

therapy, which may improve survival from meningococcal disease. 

This document has been archived for historical purposes. (7/1/2016)
Overall, the representativeness of data on cases and incidence of meningococcal disease 

among HIV-infected persons in the US is good because, while only 9% to 17% of the US HIVinfected population is represented in ABCS, the resulting data were similar to available studies 

that assessed meningococcal disease among diverse HIV-infected individuals from multiple 

countries over a time period that spanned variable HIV testing, care, and treatment. The 

representativeness of the mortality data is fair because of small numbers in ABC data, few other 

studies assessing mortality, and mixed results of those studies.

Overall, the completeness of data on cases and incidence of meningococcal disease among 

HIV-infected persons in the US is good, but there is a potential for missed cases given the many 

limitations of surveillance data to ascertain meningococcal disease among HIV-infected 

persons, including that only 9% to 17% of the US HIV-infected population is represented in 

ABCs, NNDSS does not collect HIV status of cases, and HIV testing is suboptimal. As a result, 

current data likely underestimate the true incidence of and risk ratio for meningococcal disease 

among HIV-infected persons. Completeness of mortality data is fair because if cases are 

missed due to surveillance limitations, those deaths would also be missed. Additionally, there 

are few studies investigating mortality among HIV-infected persons with meningococcal 

disease.

In summary, the WG found some limitations to its meningococcal incidence and mortality data. 

However, they feel that available data likely underestimates the true burden and mortality of 

meningococcal disease among HIV-infected persons in the US.

Turning to the outcomes evidence of benefits and harms, as a reminder, the study question 

was, “Should Men ACWY vaccine be administered routinely to all HIV-infected persons aged 2 

months and older for prevention of meningococcal disease?” The following table summarizes 

the outcomes assessed using GRADE:

Outcome

Benefits Short-term immunogenicity (4 weeks after 1st dose [week 4])

Short-term immunogenicity (4 weeks after 2nd dose [week 28])

Persistence in immunogenicity (48 weeks after 2nd dose [week 72])

Harms Serious adverse events

The WG compiled data for MenACWY vaccines in HIV-infected persons by outcome and study 

design. There were a total of 2 studies, both of which were observational, open-label trials. Of 

note, both studies assessed administration of Menactra®. One assessed administration among 

2- to 10-year old children and the other to 11- to 24-year old adolescents and young adults. 

There are no data available assessing Menveo® or MenHibrix® in HIV-infected persons.

Dr. Patton reviewed the evidence findings for benefits and harms, reminding everyone that 

these data have been presented during past ACIP meetings. Clinical effectiveness studies of 

meningococcal vaccines among HIV-infected persons are not feasible because of the low 

incidence of disease. As a result, SBA titers are used as the immunologic correlate of 

This document has been archived for historical purposes. (7/1/2016)
protection. Multiple studies have shown that SBA titers correlate with protection against 

meningococcal disease in healthy persons [Goldschneider I, Gotschlich EC, Artenstein MS. 

Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med. 1969 Jun 

1;129(6):1307-26; Andrews N, Borrow R, Miller E. Validation of serological correlate of 

protection for meningococcal C conjugate vaccine by using efficacy estimates from 

postlicensure surveillance in England. Clin Diagn Lab Immunol. 2003 Sep;10(5):780-6].

Based on the body of evidence for MenACWY vaccines in HIV-infected persons, short-term 

immunogenicity is achieved for serogroups A, C, W, and Y after both the first and second 

doses. However, immunogenicity for serogroups A, W, and Y is suppressed in HIV-infected 

adolescents aged 11 through 24 years when compared to HIV-infected children aged 2 to 10 

years after the first dose and for all serogroups after the second dose. Additionally, 

immunogenicity in HIV-infected adolescents is also suppressed when compared to healthy 

adolescents. Moreover, immunogenicity is suppressed further if there is a low CD4 count or 

high viral load. Serogroup C demonstrated the lowest rates of response and immunity.

When looking at persistence of immunogenicity at week 72, which is 1 year after receiving the 

second dose, there were higher levels of seroprotection among HIV-infected children who 

received 2 doses. However, seroprotection waned rapidly in adolescents, particularly in 

adolescents with low CD4 counts. Nevertheless, there is a boost response to the second dose.

Both studies assessed SAEs, which were reported from the time of vaccination through 6 weeks 

post-vaccination. Overall, between 2% and 7% of participants experienced an SAE event, 

including 4 laboratory events and 8 signs and symptoms including fever, headache, pain, 

psychiatric symptoms, ocular pain, and a lip lesion. SAE event rates were inversely related to 

entry CD4 percentage. Two deaths were reported in total, but both were unrelated to the 

vaccine. Of all SAEs, only ocular pain was judged to be related to the vaccine.

Based on the balance between the benefits and harms for using the vaccine, it can be 

concluded that the vaccine is immunogenic in HIV-infected children and adolescents in the 

short-term and is safe. Immunogenicity persists in HIV-infected children up to 72 weeks, but 

wanes rapidly in adolescents and young adults. Further, immune responses are suppressed 

with lower CD4 percentages or higher viral loads. The low disease burden lowers the overall 

benefits.

Regarding the determination of the evidence type for benefits and harms, in GRADE for each 

outcome, all of the available data are evaluated on the following 5 criteria and a final evidence 

type is assigned:











Risk of Bias (methodological limitations)

Inconsistency

Indirectness

Imprecision

Other considerations (publication bias, strength of association, dose response)

This document has been archived for historical purposes. (7/1/2016)
The following table describes the algorithm used to determine the final evidence type for each 

outcome. RCTs start out as an evidence type of 1 and observational studies start out as a 3. 

The 5 criteria are assessed to determine whether the overall evidence type is moved down or 

up:

No serious concerns were found for risk of bias, and no serious concerns were found with 

inconsistency for any of the outcomes. Short-term immunogenicity and persistence of 

immunogenicity were downgraded for indirectness because, while SBA titers are well-described 

and accepted as the immunologic correlate of protection in healthy persons, they have not been 

evaluated in HIV-infected persons. No serious concerns were found with imprecision for shortterm immunogenicity or persistence of immunogenicity, but SAEs were downgraded for 

imprecision since the total sample size was not sufficient to detect rare events. No serious 

problems were found for publication bias. Short-term immunogenicity was upgraded because of 

a strong strength of association and for dose response. Persistence of immunogenicity was 

upgraded because of a dose response. The final evidence type turned out to be 3 for shortterm immunogenicity after 1 dose, 3 for short-term immunogenicity after 2 doses, 3 for 

persistence in immunogenicity, and 4 for SAEs. The overall evidence type for all outcomes was 

3.

In summary, available studies demonstrate that MenACWY vaccine is immunogenic in HIVinfected children, adolescents, and young adults with immunogenicity that persists more among 

young children than among adolescents and young adults. The overall evidence type for 

benefits and harms are Type 3 with short-term immunogenicity after 1 dose, short-term 

immunogenicity after 2 doses, and persistence in immunogenicity all being type 3 and SAEs 

being Type 4.

Discussion Points

Dr. Reingold asked where there is an estimate of how many cases could be prevented 

nationally if this program was fully implemented in terms of the serogroups involved, how many 

cases there are, and the NNV to prevent a case.

This document has been archived for historical purposes. (7/1/2016)
Dr. Patton replied that she did not have this information.

Dr. Kimberlin (AAP) asked whether there are contemporary US data that document an 

increased risk of Men ACWY in HIV-infected children in the US.

Dr. Patton responded that they do not have these data. The only information on HIV-infected 

children in the US is from ABCs. There were only 2 or 3 cases between 1995 and 2014 in 

ABCs data of meningococcal disease among HIV-infected children. But again, there are very 

serious limitations to those surveillance data.

Dr. Kimberlin (AAP) said he thought it was only 1 for children under 11 years of age who would 

not be receiving the vaccine anyway at the standard age of 11.

Dr. Martin (SME) referred to Dr. Ortega-Sanchez’s Slide 22, which showed that the cases 

averted were 122 and the deaths averted were 23. That it, approximately 1 million people total 

(not per year) would have to be vaccinated to avert 122 cases and 23 deaths.

Dr. Cohn added that a very rough estimate based on the ABCs data, it is likely to be 

approximately 20 to 30 cases a year occurring among persons with HIV. That is just based on 

looking at the proportion of the population covered in ABCs, and the number of years in which 

those cases occurred.

Dr. Reingold said if those numbers were right, dividing by 70 would be about 1.5 cases per year.

In terms of the denominator, Dr. Baker (IDSA) asked how many HIV-infected children there are 

currently.

Dr. Patton replied that there are approximately 2000 HIV-infected children currently, and it is 

estimated that there are about 250 new cases of prenatally-acquired HIV per year. One would 

hope that would be decreasing over time.

Dr. Gorman (NIH) said he was struggling with the data showing the difference in mortality 

between the four countries. He asked whether they were convinced that the healthcare 

systems were that different in the four countries in terms of the engagement of the HIV 

population with antiretroviral therapy, prophylactic antibiotics, and access to healthcare.

Dr. Patton responded that they believe so, because in the two more recent studies, 80% of 

patients were on antiretroviral therapy. In the two previous studies and the earlier studies, 

almost no patients were on antiretroviral therapy.

 

Considerations for Use of MenACWY Vaccines in 

HIV-Infected Persons / Proposed Recommendations

Jessica MacNeil, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. MacNeil presented a summary of the WG discussions on meningococcal disease among 

HIV-infected persons, reminding everyone that HIV is an established risk factor for several 

bacterial infections. A growing body of evidence supports an increased risk for meningococcal 

This document has been archived for historical purposes. (7/1/2016)
disease among HIV-infected persons. ACIP does not currently include HIV-infected persons in 

the recommendations for routine vaccination of persons at increased risk for meningococcal 

disease. However, if an HIV-infected person is vaccinated, the recommendations state that 

they should receive a 2-dose primary series.

During the February 2016 ACIP meeting, the available evidence was demonstrating an 

increased risk of meningococcal disease among HIV-infected persons, MenACWY vaccine 

response in HIV-infected persons, and programmatic and other considerations for the use of 

MenACWY vaccines in HIV-infected persons were discussed. Ms. MacNeil summarized these 

data and then explained the WG’s rationale for the proposed use of MenACWY vaccines in HIVinfected persons and the proposed policy option language for a vote.

There are now five studies which have evaluated the risk for meningococcal disease among 

HIV-infected persons. Taken together, these studies consistently show an increased risk for

meningococcal disease among HIV-infected persons:

1) Stephens DS, Hajjeh RA, Baughman WS, Harvey RC, Wenger JD, Farley MM. Sporadic 

meningococcal disease in adults: results of a 5-year population-based study. Ann Intern 

Med. 1995: 123:937-40.

2) Cohen C, Singh E, Wu HM, Martin S, de Gouveia L, Klugman KP, et al; Group for 

Enteric Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). 

Increased incidence of meningococcal disease in HIV-infected individuals associated 

with higher case-fatality ratios in South Africa. AIDS. 2010; 24:1351-60.

3) Harris CM et al. Meningococcal Disease in Patients with HIV Infection-A Review of 

Cases Reported Through Active Surveillance in the United States, 2000-2008. 

Manuscript Under Preparation.

4) Miller L, Arakaki L, Ramautar A, Bodach S, Braustein S, et al. Elevated Risk for Invasive 

Meningococcal Disease Among Persons with HIV. Ann Intern Med. 2014; 160:30-38.

5) Simmons RD. et al. Risk of invasive meningococcal disease in children and adults with 

HIV in England: a population-based cohort study. BMC Med. 2015; 13: 297.

In addition to showing an overall increased risk for meningococcal disease in HIV-infected 

persons, these studies also demonstrate that among HIV-infected persons, low CD4 count or 

high viral load further increases risk. Across the studies, a similar increase in risk was observed 

for both HIV-infected men and women. One study showed that the overall risk of 

meningococcal disease in HIV-infected persons is declining along with meningococcal disease 

incidence in the US. In HIV-infected persons, meningococcal disease is primarily due to 

serogroups C, W, and Y. Overall, the data on case-fatality ratios for HIV-infected 

meningococcal disease cases is mixed. However, the more recent studies show a lower case 

fatality ratio for HIV-infected persons compared to HIV-uninfected persons.

As Dr. Patton reviewed earlier, seroresponse to MenACWY-D (Menactra®) in HIV-infected 

adolescents is suppressed compared to healthy adolescents and HIV-infected 2- to 10-yearolds. A low CD4 count or higher viral load suppresses the response even further. In addition, 

the immune response to MenACWY-D wanes rapidly. Although a boost response is seen to a 

second dose, duration of protection will likely be an issue in this population [Siberry GK, et al. 

This document has been archived for historical purposes. (7/1/2016)
Phase I/II, open-label trial of safety and immunogenicity of meningococcal polysaccharide 

diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents. 

PIDJl. 2010;29(5):391-396; Lujan-Zilbermann J, et al. Immunogenicity and safety of 1 vs 2 

doses of quadrivalent meningococcal conjugate vaccine in youth infected with HIV. J Pediatr.

2012;161(4):676-681 e672; and Siberry GK, et al. Safety and immunogenicity of quadrivalent 

meningococcal conjugate vaccine in 2- to 10-year-old HIV-infected children. PIDJ.

2012;31(1):47-52].

In addition to the evidence of increased risk for meningococcal disease in HIV-infected persons

and meningococcal vaccine response, the WG also discussed other programmatic

considerations for use of meningococcal vaccines in HIV-infected persons. There are

approximately 1 million persons living with HIV in the US1

. An additional 40,000 new HIV

infections are diagnosed each year1. Only about half of those diagnosed with HIV receive

regular HIV care2. Of those retained in care, approximately 89% are prescribed antiretroviral

therapy and 77% achieve viral suppression2

. For HIV-infected persons in care, HIV clinics

already may be administering other vaccines recommended for HIV-infected persons. HIVinfected persons in care may be more likely to have CD4 counts and viral loads favorable for

immunogenicity [

1 Centers for Disease Control and Prevention. HIV Surveillance Report, 2014. 

www.cdc.gov/hiv/library/reports/surveillance; 2 www.cdc.gov/hiv/prevention/

programs/pwp/linkage.html].

Risk for meningococcal disease among men who have sex with men (MSM) was discussed in 

detail during February’s ACIP meeting. Of meningococcal disease cases among MSM for 

whom HIV status is known, the majority (59%) are HIV-infected. This has made disentangling 

the relative contributions of HIV and MSM status to the increase in risk for meningococcal 

disease challenging in MSM populations. However, vaccinating all HIV-infected persons offers 

an opportunity potentially to impact meningococcal disease risk among MSM.

In summary, a growing body of evidence supports an increased risk for meningococcal disease 

among HIV-infected persons. Several studies have demonstrated between a 5- to 24-fold 

increased risk for meningococcal disease in HIV-infected persons compared to HIV-uninfected 

persons. In HIV-infected persons, risk is due primarily to serogroups C, W, and Y. Suboptimal 

vaccine response and programmatic challenges may limit the impact of vaccination on disease 

burden in HIV-infected persons. However, because HIV-infected persons represent a relatively 

small, defined population who receive care in a specialized medical setting, implementation of a 

recommendation in this population may be less burdensome.

The current consideration is for use of MenACWY conjugate vaccines only because in HIVinfected persons, risk appears to be due primarily to serogroups C, W, and Y. No safety or 

immunogenicity data are available for the use of serogroup B meningococcal vaccines in HIVinfected persons. Because increased risk from HIV-infection is lifelong, routine booster doses 

would be recommended for HIV-infected persons similar to other groups at increased risk.

There was strong support in the WG for including HIV-infected persons in the groups at 

increased risk of meningococcal disease who are recommended MenACWY vaccination. The 

primary considerations for the WG included the evidence of increased risk of meningococcal 

disease in HIV-infected persons and the potential benefits of vaccination in this targeted group. 

However, the WG also recognized that suboptimal vaccine response and likely issues of 

duration of protection in HIV-infected persons may limit the impact of vaccination in this group. 

There were differing opinions in the WG about the age at which to begin vaccination of HIVThis document has been archived for historical purposes. (7/1/2016)
infected persons, with some favoring 2 months and others 11 years of age. However, the 

majority of the WG members supported vaccinating HIV-infected persons beginning at 2 months 

of age.

The pros and cons of including HIV-infected children 2 months through 10 years of age in the 

recommendation were discussed by the WG. In terms of the pros, harmonizing with the current 

ACIP recommendations for use of MenACWY vaccine in persons with functional or anatomic 

asplenia or complement component deficiencies. Because the number of HIV-infected children 

in the US is small, this likely would not be a burdensome or expensive recommendation. 

Biologically, it is unlikely that the increased risk of meningococcal disease in HIV-infected 

persons differs for children and adults. The hSBA titers following 1 or 2 doses of MenACWY 

vaccine in HIV-infected children 2 through 10 years are higher than in HIV-infected adolescents 

11 through 24 years of age. Regarding the cons, depending upon the timing of doses for some 

children, the schedule may not fully harmonize with ACIP and AAPs recommendations for 

routine use of MenACWY vaccines in children 11 through 12 years of age. In addition, 

vaccination would require multiple doses over the child’s lifetime. There are limitations in the 

current data available to document the burden of meningococcal disease in HIV-infected 

children in US.

Based on the discussions of the WG, the following two policy options for use of MenACWY 

vaccines in HIV-infected persons were proposed for a vote during this session:

Option 1

Human Immunodeficiency Virus (HIV)-infected persons aged ≥2 months should routinely 

receive MenACWY vaccine* (Category A)

OR

Option 2

Human Immunodeficiency Virus (HIV)-infected persons aged ≥11 years should routinely 

receive MenACWY vaccine** (Category A)

[*Includes MenACWY-D (Menactra®), MenACWY-CRM (Menveo®), and Hib-MenCY-TT 

(MenHibrix®); **Includes MenACWY-D (Menactra®) and MenACWY-CRM (Menveo®)].

Option 1 is consistent with the current recommendations for use of MenACWY vaccines in 

persons at increased risks for meningococcal disease, including persons with functional or 

anatomic asplenia or complement component deficiencies. Option 1 was supported by the 

majority of the WG.

In addition to the recommendation language, the following guidance would be provided for use 

of MenACWY vaccine in HIV-infected persons:

 In HIV-infected persons aged 2 years of age and older who have not been previously 

vaccinated, two doses of MenACWY vaccine should be administered 2 months 

apart. For children under 2 years of age, the schedules already require multiple 

doses, and additional doses would not be recommended as part of the primary 

series.

This document has been archived for historical purposes. (7/1/2016)
 HIV-infected persons who previously received 1 dose of MenACWY vaccine would 

be recommended to receive a second dose at the earliest opportunity, and then 

would be recommended to receive boosters at the appropriate interval based on their 

age at the last MenACWY dose received.

Discussion Points

Dr. Romero did not believe that the statement about 50% of persons diagnosed with HIV 

receiving regular HIV care would apply to children. The diagnosis of HIV is made early among 

children, and he would surmise that about 80% are under HIV care. He also noted that children 

who acquire this disease perinatally comprise only 0.6% of the total 40,000. 

Ms. MacNeil replied that those numbers were for people diagnosed with HIV overall, and 

probably were much more skewed toward adolescents and adults. While she did not have the 

exact numbers for children under 13 years of age in care, she agreed that it is probably much 

higher. In addition, she thought it was probably correct that children who acquire the disease 

perinatally comprise only 0.6% of the total 40,000.

Dr. Moore pointed out that although it was noted that biologically, there is no difference between 

children and adults, differences are observed in rates of meningococcal disease that may have 

been attributed to exposure to different strains of meningococcal bacteria over time which is 

why attention is focused on older teens and young adults. Based on that, there is a sensible 

argument for starting 11 years of age even though the biology of HIV is the same. The 

behavioral risk factors associated with meningococcal disease are different.

Ms. MacNeil confirmed that the highest incidence rates are among infants and young children. 

There is an increased incidence in children less than 5 years of age, so potentially some cases 

could be prevented in that age group.

Dr. Belongia asked what the justification was for the different intervals for the booster dose for 

children under 7 years of age at 3 years versus 5 years.

Dr. Cohn replied that this was based on waning immunity from the different schedules. The 

schedules differ in young infants in terms of the number of doses versus older adults. It is 

based on the 2-dose Menactra® waning immunity data, which was substantially faster than the 

waning immunity of a single dose in adolescents.

It seemed to Dr. Thompson (NVAC) that there is a strong correlation between CD4 and 

antibodies. With respect to waning, she wondered whether the WG considered the possibility of 

booster doses related to CD4 versus just an age criterion and if there are data to support that. 

In reality in the population, there is a distribution of people with different levels of progression of 

their HIV, CD4 counts, et cetera. At some level, waning may reflect what is occurring in that 

respect. CD4 counts are regularly monitored by clinicians.

Ms. MacNeil responded that the WG did not discuss boosters related to CD4 counts, but there 

was discussion about more frequent boosters every 3 years. The thought currently is to try to 

harmonize with the recommendations for other groups at increased risk, and to continue to 

monitor cases through surveillance. If an issue is observed, more frequent boosters could be 

administered.

This document has been archived for historical purposes. (7/1/2016)
Dr. Kimberlin (AAP) expressed the AAP’s appreciation for the diligence with which ACIP had 

approached this issue. AAP’s Committee on Infectious Disease (COID) has engaged in many 

discussions as well. The focus that had been impressive to the AAP COID was listed as a con 

of dropping the age to 2 months, given the limited data to document burden of disease in HIVinfected children in the US. The AAP COID’s interpretation is that there are no data to suggest 

that. Following that, without evidence of increased risk, their discussion was focused on 11 

years of age and older.

Dr. Baker (IDSA) asked whether anyone could tell her the numbers of children in the US under 

11 years of age who have functional or anatomic asplenia or complement component

deficiencies.

Ms. MacNeil replied that the numbers are probably very small for both. In general for all ages, it 

is thought that about 1% of people have a complement component deficiency and overall about 

1 million people in the US have asplenia.

Dr. Baker (IDSA) pointed out that the good news is that there is a small number of perinatallyinfected children in the US. She thought the estimate would be that greater than 90% of HIVinfected children are in medical care. It is biologically implausible to her that children would 

have no increased risk under 11 years of age. While she hears people say that there is not a 

large disease burden or there are no data for children under 11 years of age, it seemed 

inconsistent with past and current policies to exclude a group. From a programmatic point-ofview, she thought there would be a lot of questions from the public about excluding this group at 

risk, including those at greatest risk for meningococcal disease—children less than 1 year of 

age plus HIV-infection. She indicated that the IDSA Public Health Committee favors Option 1.

Dr. Reingold was curious why one would make this recommendation for the ACWY-135 vaccine 

and not for the B vaccine. It seemed to him that serogroup B causes about a third of the cases 

in the US.

Dr. Cohn responded that the number of cases among persons with HIV are primarily serogroup 

C with some Y.

Ms. MacNeil indicated that about 80% of cases are C, W, and Y in HIV-infected persons, and 

this has been increasing recently. There are no safety or immunogenicity for MenB vaccines in 

HIV-infected people at this time. 

Vote: Use of MenACWY Vaccines in HIV-Infected Persons

Dr. Rubin motioned to approve Policy Option 1. Dr. Stephens seconded the motion. The 

motion carried unanimously with 15 affirmative votes, 0 negative vote, and 0 abstentions. The 

disposition of the vote was as follows:

15 Favored: Belongia, Bennett, Ezeanolue, Harriman, Harrison, Karron, Kempe, Moore, 

Pellegrini, Romero, Reingold, Riley, Rubin, Stephens, Walter

 0 Opposed: N/A

 0 Abstained: N/A

This document has been archived for historical purposes. (7/1/2016)
VFC Resolution

Dr. Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Santoli indicated that the purpose of this revision was to update the eligible groups for the 

use of meningococcal conjugate vaccines to include children 2 months of age and older who are 

infected with HIV. Eligible groups would include the following, which reflects the addition of

children infected with HIV:























Children aged 2 months through 10 years who are at increased risk for meningococcal 

disease attributable to serogroups A, C, W, and Y, including:

Children who have persistent complement component deficiencies (including 

inherited or chronic deficiencies in C3, C5-C9, properdin, factor H, or factor D or 

taking eculizumab [Soliris®]) 

Children who have anatomic or functional asplenia, including sickle cell disease

Children infected with Human Immunodeficiency Virus (HIV)

Children traveling to or residing in countries in which meningococcal disease is 

hyperendemic or epidemic, particularly if contact with local population will be 

prolonged (MenACWY vaccines only)

Children identified to be at increased risk because of a meningococcal disease 

outbreak attributable to serogroups A, C, W, or Y

All children aged 11 through 18 years of age.

 

No changes were recommended to the following sections of the resolution:

Recommended Vaccination Schedule and Intervals

Recommended dosage 

Contraindications and Precautions

The Serogroup B Meningococcal Vaccine component of the resolution

The standard statement regarding updates based on published documents will be included:

 

If an ACIP recommendation regarding meningococcal vaccination is published within 12 

months following this resolution, the relevant language above (except in the eligible 

groups sections) will be replaced with the language in the recommendation and 

incorporated by reference to the publication URL.

Discussion Points

Ms. Pellegrini requested clarification regarding whether the language on the booster doses 

would be incorporated by reference.

Dr. Santoli replied that she did not discuss the links included in this resolution that are not 

changed for the 2013 statement. All of the language is included through a link, and if there are 

This document has been archived for historical purposes. (7/1/2016)
changes, those are updated by reference. Links in the resolution point to the booster language 

and other language about administration of the vaccine.

Vote: VFC Resolution for the Use of MenACWY Vaccines in HIV-Infected Persons

Dr. Rubin motioned to approve the VFC Resolution for Use of MenACWY Vaccines in HIVInfected Persons. Dr. Harrison seconded the motion. The motion carried unanimously with 15 

affirmative votes, 0 negative vote, and 0 abstentions. The disposition of the vote was as 

follows:

15 Favored: Belongia, Bennett, Ezeanolue, Harriman, Harrison, Karron, Kempe, Moore, 

Pellegrini, Romero, Reingold, Riley, Rubin, Stephens, Walter

 0 Opposed: N/A

 0 Abstained: N/A

Arthur Reingold, MD

University of California, Berkeley

Chair, ACIP Evidence-Based Recommendations Work Group

Dr. Reingold indicated that the purpose of the Evidence-Based Recommendations WG is to 

provide a forum for discussion of best practices for the evidence-based recommendation 

process, including development and use of evidence tables and an evidence to 

recommendation framework to ensure consistency and enhance transparency in the 

development of ACIP recommendations, with the goal of developing a uniform approach to 

evaluation and use of the evidence base for ACIP recommendations.

The aims of the WG are potentially to modify and / or propose additional guidance for the ACIP 

evidence-based recommendation process, including GRADE and subsequent use of an 

evidence to recommendation framework, specifically to:







Identify areas for improvement and harmonization regarding development and use of 

GRADE evidence tables among ACIP WGs

Propose criteria that should be considered when determining whether GRADE evidence 

tables should be prepared for vaccine recommendations

Develop a more transparent process outlining the formulation of recommendations that 

defines methods for the incorporation of additional factors that contribute to decisionmaking, as well as GRADE evidence tables generated by systematic review

Evidence-Based Recommendations Work Group Update

This document has been archived for historical purposes. (7/1/2016)
Th













• 

• 

• 







• 

• 

e WG will develop the following:

Guidance outlining proposed modifications and/or additions to the Evidence-Based 

Recommendations approach for consideration and approval by ACIP

When developing the guidance, processes used by other nationally and internationally 

recognized groups also charged with formulating clinical and prevention policies will be 

considered 

A toolkit for use by ACIP Work Groups when formulating evidence-based recommendations

A summary of any changes to the Evidence-Based Recommendations approach used by 

ACIP for publication (e.g., in MMWR) 

Potential topics for the Evidence-Based Recommendations WG to address include the 

following:

Quality Assessment of Evidence:

Determine the optimal way to consistently include the following data when evaluating 

the evidence using GRADE:

immunogenicity data 

post-licensure safety and effectiveness assessments

data addressing the population-level impact of vaccine use

Evaluate methods to systematically and consistently evaluate burden of disease and 

outline how these data should be utilized during the process of recommendation 

development

Recommendation Development:

Develop guidance providing additional structure for the evidence to recommendation 

process, including incorporation of the following:

population-level impact of vaccine use 

values and preferences (audience, methods to elucidate such as provider 

surveys, et cetera)

Arthur Reingold, MD

University of California, Berkeley

Chair, ACIP Hepatitis Work Group

Dr. Reingold emphasized that ACIP believes it is very important to update recommendations on 

a regular basis. It has been almost 10 years since the last recommendation, although there 

have been updates in the interim. Hepatitis A recommendations were published in the MMWR

Hepatitis Vaccines Update

This document has been archived for historical purposes. (7/1/2016)
Recommendations and Reports in 2006 and Hepatitis B recommendations were published in 

MMWR Recommendations and Reports in 2005 and 2006. While there may not be a lot of new 

information or new vaccines available, the WG thinks it is important at least to update the 

statements and bring them current through 2016. The basic plan is for the WG to create two 

new documents, one on Hepatitis A and the other on Hepatitis B that will combine all of the 

information into single document that incorporates any new information. 

As a reminder, the ACIP Hepatitis WG Term of Reference are as follows:





• 

• 

• 

• 





• 

• 

• 

• 



• 

• 

Update ACIP recommendations for Hepatitis A vaccine

 

Current ACIP recommendations

ACIP Routine Recommendation for Hepatitis A Vaccine. MMWR 2006 May 

19;55(RR-7):1-23. 

Update: Prevention of hepatitis A after exposure to hepatitis A virus and in 

international travelers. Updated recommendations of the ACIP. MMWR 2007 

Oct 19;56(41):1080-4. 

FDA Approval of an Alternate Dosing Schedule for Twinrix®. MMWR 2007 

Oct 12;56(40):1057.

Updated recommendations from the ACIP for use of hepatitis A vaccine in 

close contacts of newly arriving international adoptees. MMWR 2009 Sep 

18;58(36):1006-7. 

Update ACIP recommendations for Hepatitis B vaccine

Current ACIP recommendations

ACIP Routine Recommendation for Hepatitis B Vaccine (Infants/Children). 

MMWR 2005 Dec 23;54(RR-16):1-33. 

ACIP Routine Recommendation for Hepatitis B Vaccine (Adult). MMWR

2006 Dec 8;55(RR-16):1-33.

FDA Approval of an Alternate Dosing Schedule for Twinrix®. MMWR 2007 

Oct 12;56(40):1057.

Use of hepatitis B vaccination for adults with diabetes mellitus: 

recommendations of the ACIP. MMWR 2011 Dec 23;60(50):1709-11.

Current CDC Guidelines

CDC guidance for evaluating health-care personnel for hepatitis B virus 

protection and for administering postexposure management. MMWR 2013 

Dec 20;62(RR-10):1-19.

Update: Shortened Interval for Postvaccination Serologic Testing of Infants 

Born to Hepatitis B-Infected Mothers. MMWR 2015 Oct 9;64(39):1118-20.

From May 2014 to April 2015, the WG considered Hepatitis A disease burden and population 

protection and catch-up vaccination for children / teens 2 through 18 years of age. From 

February 2016 to present, the WG has been considering immunogenicity and safety of 

HEPLISAV-B, a 2-Dose Hepatitis B Vaccine Series for Adults; and updating the ACIP 

recommendations for Hepatitis B vaccination. The ultimate goals is to develop the revised 

vaccine statements over the course of the next 6 to 12 months. They will then be presented to 

ACIP for evaluation and hopefully concurrence.

This document has been archived for historical purposes. (7/1/2016)
Dr. Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

During this session, Dr. Santoli presented an update on diphtheria, tetanus, and pertussis 

(DTaP)-containing vaccines Pentacel® and Pediarix®, and Merck vaccines in prefilled syringes.

In December 2015, Sanofi Pasteur announced a manufacturing delay with Pentacel® vaccine. 

As a result, Sanofi Pasteur is only able to meet approximately 70% of historical Pentacel®

vaccine demand. At this time, sufficient supplies of the relevant individually administered 

vaccines DAPTACEL®, ActHIB®, and IPOL® are available to address the anticipated gap in 

Pentacel® supply. Sanofi Pasteur anticipates resolution of this Pentacel® delay during the 

second half of 2016.

GlaxoSmitnKline (GSK) is experiencing a delayed release of its Pediarix® vaccine. This delay is 

anticipated to resolve in late June to early July 2016. At this time, sufficient supplies of GSK’s 

individually administered vaccines (DTaP and HepB) are available to address the gap in 

Pediarix® supply. In addition, Sanofi Pasteur has indicated it has sufficient supplies of IPV and / 

or Pentacel® vaccine to address the gap in Pediarix® supply.

The following prefilled syringes are currently unavailable:









Gardasil 9 (HPV)

Pediatric Recombivax (Hep B)

Adult Recombivax (Hep B)

Pediatric Vaqta (Hep A)

Merck anticipates return to availability in the second quarter of calendar year 2017. In the 

interim, Merck has sufficient supplies of the vial presentations for each of these vaccines to 

meet historical demand for both vial and prefilled syringe presentations.

CDC’s Vaccine Supply/Shortage Webpage can be found 

at: www.cdc.gov/vaccines/vac-gen/shortages/default.htm

Vaccine Supply

This document has been archived for historical purposes. (7/1/2016)
Introduction

Ruth Karron, MD

Chair, Influenza Work Group

Dr. Karron reported that since the February 2016 ACIP meeting, the Influenza WG has 

considered recent data pertaining to vaccine safety, FluLavalTM Quadrivalent vaccine evaluated 

in 6 through 36 months of age, the newly licensed Flucelvax Quadrivalent® vaccine, and vaccine 

effectiveness data for live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine 

(IIV). She indicated that the topics for this session would focus on vaccine safety for 2015-

2016; FluLavalTM Quadrivalent; Flucelvax Quadrivalent®; vaccine effectiveness data for 2015-

2016, including effectiveness of LAIV and IIV, from the US Influenza Vaccine Effectiveness (US 

Flu VE) Network and MedImmune; and proposed recommendations for use of influenza 

vaccines.

FluLavalTM Quadrivalent

Bruce L. Innis, MD, FIDSA

Research and Development Program for Influenza Vaccines

GSK Vaccines

Dr. Innis presented the immunogenicity and safety data for FluLavalTM Quadrivalent in children 

6 through 35 months of age. He reminded everyone that original IIVs were administered to 

young children at a reduced dose to diminish their immunogencity1-3. Most contemporary split 

or subvirion vaccines are less reactogenic in young children, but have variable immune 

responses in the age group below 3 years4-5. 

In the US, FluzoneTM is the sole IIV licensed for children 6 through 35 months of age. Its 

approved dose is 0.25 mL containing 7.5 μg of purified hemagglutinin (HA) for each of the 

strains contained in the vaccine. This is half the dose that is approved for children 3 years of 

age and older. In this development program, GSK used a 0.5mL dose containing 15μg of 

purified HA per strain of FluLavalTM Quadrivalent in the anticipation that this would improve its 

immunogenicity [1Wright PF, Thompson J, Vaughn WK, et al. J Infect Dis 1977;136:S731-41; 

2Gross PA, Ennis FA, Gaerlan PF, et al. J Infect Dis 1977;136:623-32; 3Gross PA. J Infect Dis 

1977;136:S616-25; 4Englund JA, Walter EB,Gbadebo A, et al. Pediatrics 2006;118:e579-85; 

5Walter EB, Rajagopal S, Zhu Y, et al. Vaccine 2010;28:4376-83l].

As a reminder, FluLavalTM Quadrivalent (Q-QIV) received FDA approval in August 2013 for use 

in persons 3 years of age and older. The vaccine is available in pre-filled syringes or a multidose vial. In January 2016, GSK submitted a Supplemental Biologics License Application 

(sBLA) to extend the indication to 6 through 35 months of age. The expected FDA action date 

is November 26, 2016. The dose will be 0.5mL and will contain 15μg HA from each of the 

recommended A/H1N1, A/H3N2, B-Victoria, and B-Yamagata strains. The proposed indication

follows: 

Influenza

This document has been archived for historical purposes. (7/1/2016)
FLULAVALTM QUADRIVALENT is a vaccine indicated for active immunization for the 

prevention of disease caused by influenza A subtype viruses and type B viruses 

contained in the vaccine. FLULAVALTM QUADRIVALENT is approved for use in persons 

6 months of age and older 

The sBLA contained immunogenicity and safety data generated in three small Phase 1 or 2 

studies and one very large Phase 3 trial. The development program began in 2010 and ran 

over a period of four immunization seasons. This allowed GSK to acquire safety and 

immunogenicity data on approximately 2000 subjects who were all actively monitored for safety 

for 6 months post-vaccination. Dr. Innis focused on the large pivotal Phase 3 study during this 

presentation, but emphasized that the relevance of the earlier studies is that they established 

that the profile of FluLavalTM immunogenicity and safety were consistent over multiple annual 

strain updates.

The Phase 3 study was an observer-blind randomized FluzoneTM QIV controlled trial conducted 

in 69 centers in the US and Mexico from October 2014 through June 2015. There were 2424 

children 6 through 35 months of age enrolled who appear in the total vaccinated cohort (TVC). 

Children received one or two doses according to their vaccine priming status in accordance with 

the ACIP recommendation. The strain composition of both vaccines was identical, including:









A/California/7/2009 (A/H1N1)

A/Texas/50/2012 (A/H3N2)

B/Massachusetts/2/2012 (B/Yamagata)

B/Brisbane/60/2008 (B/Victoria)

Blood samples were collected pre-vaccination and 28 days after the last vaccine dose. 

Reactogenicity data, including body temperature that was assessed using a standard digital 

thermometer, were reported by parents on a diary card daily for 7 days after dosing. Additional 

safety data were collected by the investigators at each subsequent visit with the parent or 

guardian of the study subject.

The primary protocol objective was to evaluate the immunogenic non-inferiority of FluLavalTM 

QIV versus FluzoneTM QIV in terms of geometric mean titers (GMTs) and seroconversion rates 

(SCRs) as determined by a standardized and validated hemagglutination inhibition (HI) assay

approximately 28 days after completion of dosing in children 6 through 35 months of age. The 

secondary objectives were to:









Evaluate immunogenicity of FluLavalTM QIV based on Center for Biologics Evaluation and 

Research’s (CBER’s) acceptance criteria for seroconversion and seroprotection

Describe safety and reactogenicity

Describe immunogenicity

Describe relative risk of fever for FluLavalTM QIV compared to FluzoneTM QIV within 2 days 

post-vaccination

There were no notable demographic differences in terms of age, gender, ethnicity, or 

vaccination priming status. The average age was 19.5 months. There were slightly more males 

than females. Most of the subjects were of non-Hispanic ancestry. There were approximately 

200 participants from Mexico, while the rest were from the US. There was baseline medical 

history indicating the presence of at least one risk factor that could predispose a subject to 

complications of influenza infection in 6.8% and 6.2% of subjects respectively for FluzoneTM

This document has been archived for historical purposes. (7/1/2016)
versus the comparator. The most frequent risk factor was chronic pulmonary disease, mostly 

asthma. There were 102 subjects in the younger age stratum of 6 through 17 months of age, 

and 1,422 in the older stratum. Of the subjects, 1,110 were vaccine unprimed.

While pre-vaccination titers were low and similar between the groups for all strains, the vaccine 

response for the double dose FluLavalTM treatment appeared to be slightly higher for the two B 

strains included in the vaccine. The primary confirmatory objective was to demonstrate the 

immunogenic non-inferiority of FluLavalTM QIV compared to the comparator, which was met. 

The success criteria included a GMT ratio of ≤ 1.5 for each strain and an SCR of ≤ 10% for each 

strain. The GMT ratios were < 1 for all strains in favour of the double dose treatment, although 

more so for the B strains than for the A strains. The SCR was < 6% in favour of the double 

dose FluLavalTM treatment, again notably more so for the B versus the A strain. Conformance 

with the CBER acceptance criterion for inactivated vaccines was assessed and was exceeded 

by both treatment groups, but more so for FluLavalTM. The CBER acceptability criterion for 

seroprotection was 70% of subjects who met or exceeded a titer of 1:40 by HI test following 

immunization. Both products met this criterion for 3 of the 4 strains, but neither met the criterion 

for B Victoria. The pre-immunization titers were quite low, with less than 5% of this cohort 

having a titer of 1:40 or greater. While this is presumably the explanation, Dr. Innis believes that 

the response to this strain also illustrates the potential benefits of having a double dose in the 

vaccine for this age group, because the difference is particularly notable when baseline titers 

are low.

The higher titers observed in the double dose FluLavalTM group relative to the standard of care 

prompted the investigators to perform a post-hoc analysis comparing the immune response 

elicited by the vaccine in all children and then according to age group and according to priming 

status. The post-hoc superiority analysis was performed of FluLavalTM over FluzoneTM using a 

conventional superiority criterion articulated by CBER; that is, superiority was indicated when 

the lower bound of the 95% confidence interval was > 1.5. Two important subgroups’ influenza 

B responses were superior in the double-dose FluLavalTM group: 1) children 6 through 17 years 

of age, regardless of their vaccine priming status; and 2) all children under 3 years of age who 

were not previously vaccinated. In terms of the SCR difference, in this case the superiority 

criterion for superior immunogenicity was that the lower limit of the 95% confidence interval was 

>10%. That was met again in these same two groups for the response to the influenza B 

components of the vaccine. The comparative immunogenicity data acted as a surrogate for 

vaccine efficacy.

In terms of reactogenicity data, in terms of incidence rates per subject over 7 days following 

vaccination, there were no notable differences between the treatments (any symptoms, injection 

symptoms, general symptoms) for all symptoms or Grade 3 symptoms. In addition, there were 

no notable differences between all pain, redness, and swelling and Grade 3 pain, redness, and 

swelling between the treatments. With regard to solicited general AEs for All versus Grade 3, 

because the children were young they were monitored for drowsiness, fever, irritability, and loss 

of appetite. Again, there were no notable differences. The rates of unsolicited AEs, shown in 

the following table, were equal among the treatment groups as expected and this supports the 

excellent safety profile of the new vaccine relative to what has been the standard of care for the 

last 16 years:

This document has been archived for historical purposes. (7/1/2016)
72 

FluLavalTM QIV FluzoneTM QIV

[follow up period] N = 1207 N = 1217

Any unsolicited AEs, n (%)

[28 days after vaccination] 549 (45.5%) 537 (44.1%)

Medically attended AEs, n (%)

[entire study] 727 (60.2%) 719 (59.1%)

Potential immune mediated disease, n (%)

[entire study] 1 (0.1%) 1 (0.1%)

Any SAEs, n (%) [n related]

[entire study] 22 (1.8%) [0] 21 1.7%) [0]

With respect to relative risk of fever, rates were similar between groups and the relative risk of 

fever ≥38°C was 0.97. 

In conclusion, the primary objective was met. Immunogenic non-inferiority of FluLavalTM QIV to 

FluzoneTM QIV was demonstrated for all four strains in terms of GMTs and SCR. The use of 

0.5mL dose (15μg per strain) of FluLavalTM QIV was not only immunogenically non-inferior to 

the standard of care, but also it elicited superior immune responses to both influenza B strains 

in children 6 through 17 months of age or in children 6 through 35 months of age who had not 

been vaccinated previously. Despite its double dose and injection volume, the FluLavalTM QIV

reactogenicity and safety profile was equal to that of FluzoneTM QIV. As HI antibody titer postvaccination is positively correlated with protection from influenza illness, GSK believes that 

double-dose FluLavalTM QIV may improve protection against influenza B, which is a potentially 

serious and life-threatening illness in young children. At the same time, the use of a 0.5mL 

dose (15μg per strain) FluLavalTM QIV will reduce complexity and cost in mounting the annual 

immunization campaign by allowing the same vaccine dose to be used for all persons who are 

eligible regardless of their age.

Discussion Points

Regarding fever, Dr. Walter inquired as to whether any of the children received other vaccines 

simultaneously and whether the investigators specifically assessed pneumococcal conjugate 

vaccine (PCV13). 

Dr. Innis responded that simultaneous vaccination was permitted. Though this study did not 

assess PCV13, GSK has evaluated PCV13 in the past for Fluarix® and FluLavalTM. The risk of 

fever is increased with these products and PCV, but not remarkably so. This is an acceptable 

combination.

Referring to Slide 18, Dr. Kempe noted that there was a relative risk of high fever of almost 

almost 6 and almost 3. She wondered whether the reason that was not significant was because 

there were small numbers of cases. She also inquired about the total N.

Dr. Innis replied that there were very small numbers of cases. For the relative risk of 6, there 

were 4 cases in the FluLavalTM group and 1 case in the FluzoneTM group. The total N is 

approximately 1200 subjects per group.

This document has been archived for historical purposes. (7/1/2016)
Flucelvax Quadrivalent® (ccIIV4) 

Dr. James Mansi

SeqirusTM A CSL Company

Dr. Mansi provided an update on Flucelvax Quadrivalent® (ccIIV4), the SeqirusTM quadrivalent 

inactivated cell culture influenza vaccine. This is Seqirus’sTM first influenza quadrivalent 

influenza vaccine. Flucelvax Quadrivalent® was approved by the FDA on May 23, 2016 for 

individuals 4 years of age and older.

 

Using the cell-based technology or culture platform as the SeqirusTM currently licensed 

Flucelvax Trivalent® cell culture vaccine; whereby, influenza virus is propagated in Madin Darby 

Canine Kidney (MDCK) cells, a continuous cell line. This platform provides an alternative to 

traditional influenza vaccine passage through eggs, and allows for a flexible high volume 

process without reliance on eggs. Moreover, given that the process is closed and semiautomated, the risk is reduced for external contamination.

The licensure of Flucelvax Quadrivalent® was based on the immunogenicity, safety, and 

tolerability results from two pivotal Phase III trials, both of which were conducted in the United 

States (US) during the 2013-2014 Northern Hemisphere Influenza season. The first study 

evaluated ccIIV4 in adults 18 years of age and older, while the second study evaluated ccIIV4 in 

children 4 through 17 years of age. Across both studies, ccIIV4 was shown to be immunogenic 

against all four influenza strains and demonstrated a safety profile similar to the trivalent cell 

culture vaccine, while being equally well-tolerated.

The following diagram represents the study design and subject dispensation for the adult study:

This document has been archived for historical purposes. (7/1/2016)
Approximately 2600 adults 18 years of age and older were stratified into two age groups, either 

18 through 65 years of age or 65 years of age and older. They were randomized in a 2:1:1 

fashion to receive either ccIIV4 or one of two ccIIV3 vaccines, the first having all three of the 

World Health Organization (WHO)-recommended strains for that season and the second having 

the two recommend A strains with the alternate B strain, B/Victoria. Baseline blood specimens 

were drawn at Visit 1 and again 3 weeks following immunization.

The preliminary objective of the study was to demonstrate non-inferiority of the antibody 

response from ccIIV4 compared to both ccIIV3 vaccines by the GMT ratios as well as the 

seroconversion rates. The secondary objective was to evaluate the immunologic response of 

ccIIV4 and to demonstrate superiority of the ccIIV4 on the alternate B strain. Safety data was 

collected through 6 months post-immunization.

With respect to the immune response, non-inferiority across all four vaccine strains was met by 

both seroconversion rates, whereby the upper bound of the 95% confidence interval did not 

exceed the pre-defined non-inferiority margin of 10. Similarly, for the GMT ratios, the upper 

bounds of the 95% confidence interval of each of the four strains did not exceed the pre-defined 

non-inferiority margin of 1.5. All of this confirms that the addition of the fourth influenza strain to 

the trivalent formulation did not negatively impact the immune response or the antibody 

response of the three other strains. Additionally, ccIIV4 demonstrated superiority to the 

alternate B strain compared to ccIIV3. 

In terms of the antibody response, overall the immune response was similar between ccIIV4 and

ccIIV3, with the antibody response being more robust in the younger age group of 18 through 65 

years as compared to the older age group of 65 years and older. This can be attributed to agerelated immunosenescence. The Center for Biologics Evaluation and Research (CBER) 

immunogenicity criteria were met against all strains for both HI titers >40 and the percent of 

subjects achieving sero-protective levels in the adult population of 18 through 65 year olds. In 

the adult population 65 years of age older, the CBER immunogencity criteria were met for all 

four strains for HI titers. The criteria was met for seroconversion only for the H1N1 strain. The 

lower antibody response has been observed previously in older adults in other influenza vaccine 

studies.

With respect to safety and the tolerability profile of ccIIV4 in the adult population, a similar 

percentage of subjects reported solicited AEs across all three of the vaccine groups. Overall, 

the solicited AEs were reported in a lower percentage of older adults 65 years of age and older 

as compared to the younger cohort of adults 18 through 65 years of age. The most common 

local AE was pain at the injection site, while the most common systemic AE was headaches. 

Across the entire study group, the percentage of subjects reporting unsolicited AE were few, 

with similar rates across each of the three vaccine groups. SAEs were reported in about 1% of 

subjects, with none found to be related to the vaccine. Thus, the reactogenicity and safety 

profile of Flucelvax Quadrivalent® were consistent with those of the SeqirusTM trivalent cell 

culture vaccine in the adult population, and similar to what is observed in other influenza 

vaccines in this adult population.

This document has been archived for historical purposes. (7/1/2016)
The pediatric study included approximately 2300 children 4 through 17 years of age who were 

stratified into two age groups, children 4 through 8 years of age and children 9 through 17 years 

of age shown in the diagram below:

Within these strata, subjects were randomized to receive vaccine in a 2:1:1 fashion to receive

either ccIIV4 or one of two ccIIV3 vaccines, the first having all three of the WHO-recommended 

strains for that season and the second having the two recommend A strains with the alternate B 

strain, B/Victoria. Previously vaccinated children received one dose; whereas, influenza 

vaccine naïve children received two doses one month apart. Baseline blood samples were 

taken at Visit 1 and again 1 month following the last dose of study vaccine. Similar to the adult 

study, a primary objective of this study was to demonstrate non-inferiority of ccIIV4 against the 

GMT ratio and seroconversion rates compared to ccIIV3. The secondary objectives included 

the antibody response of ccIIV4 compared to ccIIV3 according to CBER and the Committee for 

Medicinal Products for Human Use (CHMP) criteria, and demonstration of superiority of ccIIV4

to the alternate B strain. Once again, safety was followed up through 6 months following the 

last dose of study vaccine.

The immune response to the cell culture vaccine was shown to be non-inferior for both the 

seroconversion rates, where the confidence intervals for each of the four influenza strains were 

below the pre-defined non-inferiority margin of 10. For GMT ratios, all four of the vaccine 

strains were shown to be non-inferior below the pre-defined non-inferiority margin of 1.5. Once 

again, superiority of ccIIV4 was demonstrated in the population of children 4 through 18 years of 

age against the alternate B strain in the vaccine. In terms of the antibody response, overall the 

immune responses were similar between ccIIV4 and each of the trivalent cell culture vaccines. 

The CBER criteria for immunogenicity based on seroconversion and HI titers >40 were met in 

children 4 through 18 years of age for all four of the influenza strains in the vaccine. The 

European CHMP criteria were equally met for seroconversion and HI titers.

This document has been archived for historical purposes. (7/1/2016)
With respect to safety and tolerability of ccIIV4 in this pediatric population, overall the safety 

profile was similar to that of the comparator trivalent cell culture vaccines and to what has been 

observed in other influenza non-cell culture vaccines, including similar reactogenicity profiles. 

The reported solicited AEs were generally mild to moderate in nature and of a limited duration, 

resolving in less than 7 days. The most common local AEs reported were tenderness and 

injection site pain across all of the vaccine groups in equal proportions. The most common 

systemic AEs reported were sleepiness, fatigue, and headache across all three of the vaccine 

groups. Unsolicited AEs were reported in about 24 percent of subjects equally across each of 

the three vaccine groups. None of those were judged by the investigators as possibly related to 

any of the vaccines, and were comparable across all three. SAEs were reported in about 1% of 

all subjects and were equally distributed across each of the three vaccine groups, and none 

were judged by the investigators as vaccine-related.

In conclusion, the cell culture-based platform represents an alternative to traditional egg-based 

vaccine platforms, allowing for a flexible, high-volume process without relying on eggs. Given 

that it is a closed, semi-automated process, risk for external contamination is limited. What has 

been shown in the clinical trials for ccIIV4 is that from an immune perspective, ccIIV4 was able 

to illicit an immune response that was non-inferior to the comparator ccIIV3 and provided a 

superior immune response to the alternate B vaccine. The safety profile of MDCK cell-derived 

QIV was similar to that of TIVc vaccines, including a similar reactogenicity profile. No 

unexpected safety signals or concerns occurred throughout the study across the various ages.

 

Discussion Points

Dr. Gorman (NIH) requested an estimation of the time advantage over egg-based 

manufacturing processes in terms of a pandemic, and an estimation of SeqirusTM production 

capacity.

Dr. Mansi replied that the cell-based platform allows for more flexible and rapid production of 

influenza vaccine, particularly in a pandemic. They have run estimates on pandemic readiness, 

which he indicated he would share with ACIP. In terms of production capacity, SeqirusTM is able 

to meet current demands. 

Dr. Belongia said he thought it was important to acknowledge that although manufacturing 

occurs in cell culture, it begins with egg-adapted viruses as a source and does not eliminate the 

problem of using eggs completely. Mutations can occur during egg adaptation. For the adult 

study, he wondered whether Dr. Mansi had any data on the proportion of participants who 

received vaccine the previous year and if so, whether there was a distribution of some people 

who were and were not vaccinated in the prior year.

Dr. Mansi noted that the full potential of the cell-based platform would be reached once they 

reach the starting point with the virus in the cell basing. The majority of adults were previously 

vaccinated, so a high number of adults had seroprotective levels at baseline, particularly in the 

older adult population that was equally distributed among the three vaccine groups.

This document has been archived for historical purposes. (7/1/2016)
Vaccine Safety Update

Tom Shimabukuro, MD, MPH, MBA

Immunization Safety Office

Centers for Disease Control and Prevention 

Dr. Shimabukuro shared the following table depicting the influenza vaccine products utilized 

during the past season, pointing out that IIV is commonly used when speaking of inactivated 

products collectively or some group of inactivated products, while all LAIV is quadrivalent.

Vaccine Abbreviation

Trivalent inactivated influenza vaccine IIV3

Quadrivalent inactivated influenza vaccine IIV4

Quadrivalent live attenuated influenza vaccine LAIV4

High-dose trivalent inactivated influenza vaccine IIV3-HD

Intradermal trivalent and quadrivalent inactivated influenza vaccines IIV3-ID

IIV4-ID

Cell culture-based trivalent inactivated influenza vaccine ccIIV3

Recombinant trivalent inactivated influenza vaccine RIV3

He reminded everyone that the Vaccine Adverse Event Reporting System (VAERS) is a passive 

reporting system that is administered by the CDC and FDA. The strengths are that it includes 

national data, is good for rapid signal detection, and can detect rare AEs. The limitations are 

the limitations inherent to passive surveillance in general, including reporting bias, inconsistent 

data quality and completeness, lack of unvaccinated comparison group. Because of this, 

whether a vaccine caused an AE generally cannot be assessed from VAERS data.

Included for this season were US influenza vaccine reports received in VAERS through May 27, 

2016 for individuals vaccinated July 1, 2015 through May 6, 2016. Signs, symptoms, and 

diagnoses are coded using the Medical Dictionary for Regulatory Activities (MedDRA) terms. 

Clinical review of reports, which includes review of medical records when available, were 

performed for the following: 







All serious reports after IIV4, IIV4-ID, LAIV4, ccIIV3, RIV3

All anaphylaxis reports in persons with a history of egg allergy

Pregnancy reports for spontaneous abortion, stillbirth, congenital anomalies, and serious 

pregnancy reports

This document has been archived for historical purposes. (7/1/2016)
Empirical Bayesian data mining was also conducted. Serious reports are based on the Code of 

Federal Regulations and include death, life-threatening illness, hospitalization or prolongation of 

hospitalization, or permanent disability. 

Following IIV3, IIV4, LAIV4, and IIV3-HD in 2015-2016, serious reports were 5% to 6% and nonserious reports were 94% to 95%. Keeping in mind that VAERS is a passive system, the 

percentage of serious reports is the percentage of all reports that met the regulatory definition 

for “serious” that were submitted to VAERS. It is not the rate of SAEs after influenza 

vaccination, which is very low based upon the clinical trials. These percentages of breakdowns 

for serious and non-serious events are similar to other vaccines in the VAERS database. 

Guillain-Barré Syndrome (GBS) reports comprised a very small percentage of total reports from 

0.5% to 1% for these products. That is similar to what was observed last year. Anaphylaxis 

reports are rare in VAERS, ranging from 0.3% to 0.6%. There were two reports of anaphylaxis 

following LAIV4 in persons with a history of egg allergy. One was in an adult who received 

LAIV4 alone, while the other was in a child who received multiple other vaccines during the 

same visit. There were no data mining findings for GBS or anaphylaxis. Following ccIIV3, 

RIV3, IIV3-ID, and IIV4-ID overall similar observations were made. There were no data mining 

findings for GBS or anaphylaxis for these influenza products either.

There was a total of 58 reports of pregnancy in VAERS for the season following IIV3 or IIV4. 

The median maternal age was 32 years, with a range of 14 through 44 years of age. 

Gestational age was reported in 17 (29%) cases. The median gestational age was 20 weeks, 

with a range of 4 to 38 weeks. The breakdown for the 17 reports was approximately one-third 

for each trimester. Of the 58 reports, 8 included pregnancy-specific outcomes or 14% of the 

total reports. There were 5 spontaneous abortions, 1 stillbirth, and 2 cases of vaginal bleeding. 

The overwhelming majority of reports either were non-pregnancy specific such as injection site 

reactions and other non-pregnancy specific events, or no AE report. There was a total of 7 

LAIV4 reports, none of which included any pregnancy-specific events. In fact, 5 of the 7 had no 

AE. 

In summary of VAERS surveillance for the 2015-2016 influenza season, no new safety 

concerns were detected for IIVs, LAIV4, ccIIV3, or RIV3. Surveillance for the 2016-2017 

influenza season will include enhanced safety monitoring for the following: 









Adjuvanted influenza vaccine (Fluad®) 

IIV4-ID (Fluzone® Intradermal Quadrivalent)

Pregnancy reports

Anaphylaxis reports in persons with a history of egg allergy

Turning to FDA near real-time surveillance, for GBS following influenza vaccination in Medicare 

beneficiaries for the 2015-2016 influenza season, 

FDA conducts near real-time surveillance for GBS following influenza vaccination every 

influenza season in collaboration with CMS. 

Weekly statistical testing compares GBS rates in the current season with rates in the prior three 

seasons in the Medicare database. During 2015-2016 season, there were 15.4 million IIV 

administrations. This includes all IIV products combined comprised primarily of standard dose 

IIV3, IIV4, and High-Dose IIV.

This document has been archived for historical purposes. (7/1/2016)
FDA’s 2015-2016 season surveillance showed a GBS rate increase following IIV of small 

magnitude, with 7.25 cases/million IIV vaccinees in comparison to an average of 5.45 

cases/million IIV vaccinees for the past three seasons. The limitations of surveillance include

the fact that it was a comparison of current to historical data, this is a claims-based analysis, 

there was a change from ICD-9 in the previous seasons to ICD-10 in the 2015-2016 season, 

and there was no control for confounders. End-of-season analysis using self-controlled designs 

has been initiated. 

As a reminder, the Vaccine Safety Datalink (VSD) was established in 1990 and is a 

collaboration between CDC and 9 integrated healthcare plans. VSD collects data on over 9 

million persons per year, which is approximately 3% of the US population. VSD links 

vaccination data to health outcome data. VSD includes vaccination records; health outcomes 

from hospitalizations, emergency department (ED) visits, and outpatient encounters; and 

information on patient characteristics. These are all linked by unique identifiers into a large 

linked database that CDC uses for surveillance and epidemiologic studies.

The outcomes assessed for the end-of-season analysis for 2015-2016, which are the same as 

assessed last season, are shown in the following table:

Pre-Specified 

Outcome Age Group Risk Window(days)

Control Window*

(days)

Anaphylaxis >6 mos 0-2 7-9

Bell’s palsy

>6 mos to <18 yrs

18-49 yrs

>50 yrs

1-42 -56 to -15

Encephalitis >6 mos 1-21 -56 to -15

Guillain-Barré 

syndrome >6 mos 1-42 43-84

Seizures 6-23 mos

24-59 mos

0-1 for IIV

0-14 for LAIV

14-20 for IIV

15-29 for LAIV

Transverse myelitis >6 mos 1-21 -56 to -15

In terms of the number of Dose 1 doses administered in the VSD for this season, there were 

roughly 3.2 million IIV doses and relatively small amounts of vaccine doses administered for the 

other products. Because of this, the end-of-season focused on IIV3. There is not enough data 

on the other products to achieve meaningful results.

 

Because of the transition from ICD-9 to ICD-10 in 2015, VSD analysis was limited to analysis of 

ICD-10 data, specifically IIV3 doses administered after October 1, 2015. A self-controlled risk 

interval (SCRI) analysis was conducted. There was a concern about the transition from ICD-9 

to ICD-10 and how that might impact the analysis, so the decision was made to assess ICD-10 

data only for the current season using an SCRI design, which avoids the problems of the current 

versus historical ICD-10 versus ICD-9 issues. GBS was the signaling outcome in the 2015-

2016 season. The risk window for GBS in this analysis was Days 1 through 42 (the biologically 

plausible risk interval) and the comparison window was days 43 through 84. The incident 

definition was “first occurrence in a year.” The SCRI design assesses vaccinated cases only, 

This document has been archived for historical purposes. (7/1/2016)
each patient serves as his or her own control, and the goal is to look for events in the risk 

window and events in the comparison window.

For those greater than 6 months of age, there were 27 cases in the risk window and 4 in the 

comparison window. That is a relative risk of 3.38, which is statistically significant. In those less 

than 65 years of age (6 months through 64 years of age), there were 14 cases in the risk 

window and 4 cases in the comparison window. That is a relative risk of 3.5, which is 

statistically significant. In individuals 65 or more years of age, there were 13 cases in the risk 

window and 4 cases in the comparison window. That is a relative risk of 3.25, which is 

statistically significant. The next model assessed inpatient or ED encounters for all individuals 

greater than 6 months of age. There were 18 cases in the risk window and 6 in the comparison 

window. The relative risk is 3, which is statistically significant. A quick chart review was 

performed for inpatient or ED encounters in those greater than 6 months of age. The quick 

chart review included an electronic medical record review to confirm a case as an incidence 

case, with a diagnosis by a neurologist. The relative risk was 3.67, which was statistically 

significant. In terms of the general results from the 2014-2015 season for all ages, there were 

18 cases in the risk window and 13 in the comparison window. The relative risk was 1.38, 

which was statistically significant. The take-home message is that, for the current season 

assessing the risk of GBS associated with IIV using various models with different ages and 

different settings and conducting a quick chart review, a statistically significant relative risk is 

consistently being observed of 3 to 3.6 in this preliminary analysis.

The following chart reflects the GBS SaTScanTM clustering results in the VSD using automated 

data for the 2015-2016 influenza season: 

In summary, VSD identified a significantly elevated relative risk of 3.67 (95% CI: 1.02, 13.14) 

using the SCRI method in the quick chart review analysis. The corresponding attributable risk 

for GBS following IIV3 is approximately 2.6 additional GBS cases per million doses 

administered. VSD will continue to further evaluate the association by conducting chart reviews 

of all GBS cases (inpatient, emergency department and outpatient), and by conducting a casecentered analysis that adjusts for seasonality of both IIV3 administration and of GBS and other 

potential confounders. 

This document has been archived for historical purposes. (7/1/2016)
To summarize influenza safety monitoring for the 2015-2016 season, no new safety concerns 

were detected in VAERS surveillance. FDA surveillance for GBS following influenza vaccination 

in Medicare beneficiaries showed a GBS rate following IIV of 7.25 cases per million compared 

to an average of 5.45 for the prior three seasons. Further assessment using self-controlled 

methods is in progress. For CDC VSD end-of-season analysis, a signal was identified for GBS 

following IIV3 in the SCRI design. Estimated attributable risk is 2.6 GBS cases per million IIV3 

doses administered. Signal assessment using detailed chart review and case-centered analysis 

is in progress. The preliminary GBS risk estimate appears consistent with that observed in 

some previous influenza seasons. 

 

In conclusion, the association between IIV and GBS is not new. This has been observed in the 

past. The data have been variable across seasons. If there is an increased risk, it is small on 

the order of 1 to 2 additional cases per 1 million doses administered. The preliminary risk 

estimates observed for this season is similar to what has been observed in some past seasons. 

The CDC and FDA need to perform additional assessments on these signals. The findings 

need to be placed in the context of the known benefits of influenza vaccination in preventing 

disease and complications from influenza. Influenza disease is actually a risk factor for GBS.

Discussion Points

Noting that introduction of newer vaccines such as the quadrivalent high-dose might have some 

safety implications, Dr. Kempe asked what percent of the FDA data included quadrivalent or 

high-dose.

Dr. Shimabukuro responded that CDC monitors those vaccines, but the data are so sparse 

there are not meaningful results. He did not have the breakdown of that information for the 

FDA, but indicated that he could follow up with them.

Dr. Karron asked for a reminder of the risk associated with GBS as associated with influenza 

infection.

Dr. Shimabukuro said that while he did not have exact numbers, there are pretty wellestablished risk factors for GBS, including upper respiratory illnesses, of which influenza is one; 

gastroenteritis, specifically campylobacter; surgery; age; pregnancy; and others.

Dr. Bennett asked if there was an estimation of what percentage of GBS cases might be 

associated with influenza vaccine.

Dr. Shimabukuro said that while he did not know specifically, when studies have controlled for 

influenza disease, it has basically lowered the risk. The risk went away.

Dr. Stephens asked whether the question with ICD-9 and ICD-10 was a sensitivity issue.

Dr. Shimabukuro responded that his understanding was that it is a one-to-one, or a single 

outcome compared to a single outcome. The ICD-9 diagnosis was acute infective polyneuritis, 

while the ICD-10 diagnosis is GBS. If anything, the ICD-10 should be a better code. Based on 

the preliminary work done, this does not seem to be impacting the surveillance. CDC has work 

underway to assess the impact in general of the ICD-9 to ICD-10 transition.

This document has been archived for historical purposes. (7/1/2016)
Dr. Moore said that from work done in her state and others, in efforts to correlate claims data 

with actual medical records, there is not good correlation between the diagnosis according to 

the claims data and the medical record review. She noted with pleasure that the final results 

involve actual record reviews to confirm the diagnosis of GBS in doing these assessments. 

Obviously, with such small numbers over millions of doses administered, it can swing one way 

or the other very easily. She asked when those data would be available.

Dr. Shimabukuro replied that he was uncertain when the results would be available. He will 

have to follow-up with FDA. CDC is in the process of reviewing the cases, but he did not have a 

specific hard date on when the reviews and the case-centered analysis would be completed.

Dr. Walters asked whether the years in which the association had been seen happened to track 

with any predominant strains circulating that year. He wondered whether it pertained to 

circulating disease or the vaccine strain.

Dr. Shimabukuro responded that the last time an increased risk was observed was during the 

pandemic, which was with monovalent H1N1. However, it was not observed in seasonal 

vaccine that year. This is the first time since the pandemic that an increased risk has been 

observed for GBS. It is the first time an increased risk has been observed with H1N1-containing 

seasonal vaccines. Therefore, options are being explored to determine how to further assess 

multiple years of data. There was a strain change in the past season. It was the same for the 

two prior seasons. There was a strain change in the As and one of the Bs for this season. The 

vaccine changes year-to-year, and it is not unreasonable to think that there may be differences 

in reactogenicity based on changes in the vaccine. However, it is not clear whether these 

findings could be attributed to any strain change.

Dr. Gorman (NIH) noted that the increased number of cases in the 2009 monovalent was 

approximately 1 case per million doses, so about half. Recognizing all of the confounders 

already mentioned, he thought that they were in the same range for monovalent.

Dr. Shimabukuro responded that several studies showed increased risk. In the meta-analysis, it 

was 1.6 and this is 2.6. If there is an increased risk, it is on the order of 1 to 2 additional cases 

per million doses administered.

Dr. Gorman (NIH) asked when the diagnosis of GBS is made—the day the symptoms start or 

the day the diagnosis is made for attributing the diagnosis.

Dr. Shimabukuro replied that there are automated analysis and chart confirmed analysis. For 

automated analysis, it is really based on the dates in the administrative database. When a chart 

confirmation is done, an effort is made to pinpoint symptom onset to determine if that is an 

incident case.

Dr. Gorman (NIH) pointed out that GBS, like most diseases, has a distribution of seriousness. 

He asked whether Dr. Shimabukuro had any sense of whether GBS after influenza vaccination 

is more or less severe than GBS in general.

Dr. Shimabukuro responded that there is not a difference in the severity of course regardless of 

whether it occurs after vaccination or is a spontaneous case.

This document has been archived for historical purposes. (7/1/2016)
Dr. Middleman (SAHM) thought there was a similar issue of GBS that was initially associated 

with meningococcal vaccination, and then it was found that the campylobacter season was 

playing a role. She asked whether Dr. Shimabukuro felt that by using self-controlled analysis 

this is a potential risk in that vaccination was probably given during that same kind of season 

and that by using self-controls, they may have left the campylobacter season. 

Dr. Shimabukuro replied that there is seasonality to GBS. One reason CDC is conducting the 

case-centered analysis is because that controls for seasonality of GBS. It is possible that 

seasonality is a confounder, but that is part of the assessment.

Dr. Thompson (NVAC) asked how reports are made to the VSD and whether there is a potential 

that things that happen later in the context of a patient’s time since the vaccine might have less 

likelihood of being reported, or whether there was no concern about reporting bias to the VSD.

Dr. Shimabukuro responded that VAERS is a spontaneous reporting system that depends upon 

people to send in reports. VSD is a large linked database that utilizes electronic health records, 

so no one is actually reporting into VSD. These data are captured in the health systems 

administering people’s health insurance programs. While there may be biases to VSD data. 

Reporting bias should not be one of them.

Vaccine Effectiveness Update

Dr. Brendan Flannery

Influenza Division

Centers for Disease Control and Prevention

Dr. Flannery reviewed end-of-season estimates of influenza vaccine effectiveness for the 2015-

16 season from the US Flu VE Network, and presented data comparing LAIV and IIV 

effectiveness among children and adolescents aged 2 through 17 years during the season. 

In terms of the end-of-season estimates, the percentage of visits for influenza-like illness (ILI) by

week from the Influenza-Like Illness Surveillance Network (ILINet) over the past 6 seasons 

since the 2009-2010 season shows the late increase in ILI activity observed in the 2015-2016 

season, with peak ILI activity occurring in March. This is one of the few seasons that has had a 

peaked in March. Influenza A/H1N1pdm09 virus predominated with circulation of both B virus 

lineages.

The US Flu VE Network, funded by CDC, conducts annual studies of influenza vaccine 

effectiveness at five sites within the US, shown in on the following map along with the Principal 

Investigators (PIs) at each site:

This document has been archived for historical purposes. (7/1/2016)
Of note, the same sites have participated in the US Flu VE network over the past 5 influenza 

seasons. To briefly review methods for the VE estimates presented during this session, US Flu 

VE network sites enroll outpatients 6 months of age and older who present with an acute 

respiratory illness with cough of 7 or fewer days duration. This analysis includes patients 

enrolled from November 2, 2015 through April 15, 2016. All enrolled patients are tested for 

influenza by reverse transcription-polymerase chain reaction (RT-PCR). VE estimates are 

based on the test-negative design, comparing vaccination odds among influenza PCR-positive 

cases versus PCR-negative patients as the control group. For this analysis, vaccination is 

defined as receipt of at least one dose of any 2015-2016 influenza vaccine and includes partially 

vaccinated children. Vaccination status was determined from medical records, immunization 

registries, or self-report with plausible timing and location of immunization, referred to as 

plausible self-report, for patients aged 9 years and older. VE is estimated as 1 minus the 

adjusted odds ratio times 100%. Odds ratios were adjusted for study site, age, self-rated 

general health status, race/Hispanic ethnicity, interval (days) from onset to enrollment, and 

calendar time. 

A total of 7,563 patients were enrolled during the season, of whom 82% were influenza negative

(controls) and 18% were influenza positive. The predominant influenza virus among enrolled 

patients was A/H1N1pdm09, with cases due to both B lineages and only 6% of confirmed cases 

due to A/H3N2, the predominant virus during the 2014-2015 season. All viruses from enrolled 

patients that were antigenically characterized were similar to vaccine reference viruses, with 

limited genetic variability among H1N1pdm09 or B viruses, and mixed circulation of two clades 

of H3N2 viruses, all characterized as vaccine-like.

The overall adjusted VE estimate for all vaccines was 47% with 95% confidence interval from 

39% 53%. VE estimates were statistically significant for patients of all ages with the exception 

of adults aged 50 through 64 years. Restricting to inactivated vaccines only, adjusted VE was 

49%, very similar to the estimate for all vaccines. The adjusted VE against illness associated 

with A/H1N1pdm09 virus was 41%, with 95% confidence interval from 31% to 51%. Again, VE 

was statistically significant for all ages except adults aged 50 through 64 years. Restricting to 

inactivated vaccines, adjusted VE was 44%. For all ages combined, adjusted VE against 

A/H3N2-related illness was 45% with confidence intervals from 9% to 66%. For B Yamagata 

viruses, adjusted VE was 55% with confidence intervals from 41% to 66%, and for B Victoria 

This document has been archived for historical purposes. (7/1/2016)
lineage viruses, adjusted VE was 55% with confidence intervals from 38% to 68%. Estimates 

restricted to inactivated vaccines were similar to overall estimates.

Over 2000 children were included in the analysis of LAIV and IIV effectiveness among children 

2 through 17 years of age by influenza virus type and subtype. Of these, 18% were influenza

positive and almost half of the influenza cases were H1N1pdm09, with somewhat higher 

numbers of B/Victoria lineage viruses than B/Yamagata. Regarding the methods for this 

analysis, vaccination was defined as at least one dose, including partially vaccinated children. 

Only documented doses were considered for children 2 through 8 years of age. Documented 

doses and plausible report of vaccination were considered vaccinated for those 9 through 17 

years of age. Vaccine type was determined from medical record or parent report if the record 

had no information. Odds ratios were adjusted for study site, age, and listed variables, including 

calendar time in biweekly intervals. Of note is that because of the importance of this analysis 

this season, all analyses were independently confirmed by Jessica Pruszynski at Baylor Scott & 

White Health. A total of 154 enrolled children were excluded from this analysis, primarily 

because their illness onset occurred prior to confirmed influenza circulation at that site, or illness 

onset occurred within 14 days of vaccination. 

In terms of adjusted VE estimates for LAIV and IIV among children 2 through 17 years of age

against any influenza A or B and for A/H1N1pdm09-related illness and by B lineage, estimated 

LAIV effectiveness against any influenza was 3% with confidence intervals including zero. 

Estimated IIV effectiveness was 63% with a confidence interval from 52% to 72%. Estimates for 

LAIV effectiveness against A/H1N1pdm09 and B viruses were not statistically significant, while 

estimates for IIV were similar to the VE estimate against any influenza. Among children 2

through 8 years of age, no significant VE was demonstrated against any influenza, 

A/H1N1pdm09 or influenza B. The lowest point estimates were observed against 

A/H1N1pdm09 viruses. Similarly, estimates of LAIV effectiveness were not significant among 

patients 9 through 17 years of age, although the point estimate for VE against A/H1N1pdm09 

was higher than among children 2 through 8 years of age. The adjusted odds of influenza was 

also estimated of influenza among LAIV versus IIV vaccinated children similar to an analysis or 

relative effectiveness, excluding unvaccinated children. In this analysis, children who received 

LAIV had significantly higher odds of influenza due to any virus type or due to A/H1N1pdm09 

compared to IIV vaccinated children. Odds ratios greater than 1 favor IIV. The result for 

influenza B was not statistically significant.

In addition to US Flu VE data, data also were received from the Department of Defense (DoD) 

laboratory-based influenza surveillance system. These data include military dependents 2

through 17 years of age who presented to participating facilities during the 2015-2016 season 

with ILI. Laboratory testing by clinical indication was by RT-PCR or culture, and the study used 

a test-negative design with RT-PCR negative controls. Vaccination status was determined from 

electronic medical records. The estimates were adjusted for two age groups and 3 time periods 

during the season. Regarding adjusted VE estimates for military dependents 2 through 17 

years of from the DoD laboratory-based influenza surveillance system, estimated VE against 

A/H1N1pdm09 associated illness for LAIV was 15% with confidence intervals including zero. 

Estimated VE for IIV against A/H1N1 was 68% and was statistically significant. Numbers of 

influenza positive cases among vaccinated children were small for A/H3N2 and B, but estimated 

VE against influenza B was statistically significant for both LAIV and IIV in this system [Lt. Col. 

Susan Federinko, US Air Force].

This document has been archived for historical purposes. (7/1/2016)
This analysis is subject to limitations. First, the final end-of-season analyses are pending, since 

prior season vaccination status is pending for one site and chronic conditions were not included 

in adjusted estimates. However, data were received from all five sites for prior end-of-season 

vaccination and chronic conditions. Those will be included in updated analyses, which have 

been run already and did not change the results presented during this session. In previous 

seasons, final analyses have been similar to preliminary end-of-season results. Secondly, there 

is limited precision for some VE estimates due to small numbers of influenza cases in some 

strata.

In summary, the 2015-2016 influenza season was a late season, with peak enrollment at US Flu 

VE network sites in March and mixed circulation of A/H1N1pdm09 and B viruses. Overall 

vaccine effectiveness for any vaccination was 47% against influenza A and B. Point estimates 

were 41% for A/H1N1pdm09 and 55% for B viruses. Vaccine effectiveness for LAIV was 

significantly lower than IIV among children 2 through 17 years of age. No significant LAIV 

effectiveness was observed against A/H1N1pdm09 or B viruses. Relative effectiveness 

significantly favored IIV over LAIV against A/H1N1pdm09-associated illness. 

2015-16 US Influenza Vaccine Effectiveness

Influenza Clinical Investigation for Children (ICICLE) Study 

Chris Ambrose, MD

Vice President, Infectious Disease

US Medical Affairs, MedImmune

The Influenza Clinical Investigation for Children (ICICLE) VE study demonstrated significant 

overall VE for LAIV4 and IIV in US children 2 through 17 years of age in 2015-2016. For LAIV4, 

VE was 46% (95% CI: 7, 69) and for IIV VE was 65% (95% CI: 48, 76). Supporting those 

results are similar results in a 2015-2016 in a test-negative VE study in the United Kingdom 

(UK) and a large cohort study in Finland. Including the DoD study just presented, these LAIV4 

VE estimates are similar to VE observed with IIV in children in recent seasons (e.g., 2011-2012 

and 2012-13)1-3

Reduced effectiveness has been observed this last season relative to IIV vaccine for LAIV. But 

the range of the point estimates in these studies is within the range observed in other seasons. 

There is no explanation at present for the difference between these studies compared to the 

CDC LAIV4 VE estimate, particularly because the CDC and ICICLE study methods are very 

similar and in past seasons have reached similar estimates of effectiveness. The differences 

may relate to a limited sample size (less than 150 children have received LAIV), statistical 

power, or limitations of observational study design [1Ohmit et al, CID 2013; 2McLean et al, JID, 

2014; 3Flannery B. ACIP presentations. 2014]. Similar to the CDC VE study, ICICLE is an 

observational, test-negative design. Community-dwelling children 2 through 17 years of age 

were enrolled at the following US sites:















Marshfield Clinic, Wisconsin (Edward Belongia)*

Baylor Scott & White Health, Texas (Manjusha Gaglani)*

Vanderbilt University, Tennessee (Marie Griffin)

Wake Forest University, North Carolina (Katherine Poehling)

Akron Children’s Hospital, Ohio (Blaise Congeni)

HealthPartners Como Clinic, Minnesota (Poornina Kavathekar)

Kaiser Permanente, Oregon (Allison Naleway)

This document has been archived for historical purposes. (7/1/2016)
 University of Florida, Gainesville (Kathleen Ryan)

Children are enrolled who are seeking outpatient care for febrile acute respiratory illness with 

onset <5 days. Like the CDC study, subjects are excluded who were vaccinated <14 days 

before symptom onset. Nasal swabs are tested by PCR using a respiratory viral panel. This is 

a subtle difference from the CDC study in that MedImmune knows the outcome for influenza 

and other respiratory viruses, which allows them to perform an important secondary analysis 

comparing cases being influenza positive to controls being positive with another respiratory 

virus. That was in addition to the study requested by the FDA, because this is an FDA postmarketing commitment study. Sites are monitored up to 3 times per season to confirm data 

accuracy. That is important to ensure good clinical practice and because it is an FDA postmarketing commitment. Like the CDC study, the Medimmune study results were independently 

analyzed [*Also participate in CDC VE study but at different clinic sites, so the same patients 

are not being enrolled].

The ICICLE study enrolled 1,238 children from November 30, 2015 to April 15, 2016. Of these, 

226 were excluded from analysis for the following reasons: 









Enrolled before or after influenza circulation: n=215

Vaccination <14 days before illness: n=7

Missing documentation of vaccination date and/or type: n=3

Lack of signed consent: n=1

This resulted in 1,012 subjects being retained for analysis. Of these, 594 were unvaccinated 

children, 101 were LAIV4 recipients, and 317 were IIV recipients. 

The 2015-2016 ICICLE population characteristics by vaccine group are delineated in the 

following table:

 

No Vaccination

(n=594)

LAIV4

(n=101)

IIV

(n=317)

2 to 4 years

5 to 8 years

9 to 17 years

28%

36%

36%

33%

47%

20%

36%

36%

28%

Privately insured 45% 56% 53%

Chronic condition 16% 6% 26%

Prior vaccination in 2014-2015 32% 73% 77%

This is an observational study, so there are differences in the children who were unvaccinated 

versus those whose parents elected to receive LAIV4 versus those who elected to receive IIV. 

Some of the greatest differences are illustrated in the table in terms of age, insurance status, 

chronic conditions, and prior vaccination.

This document has been archived for historical purposes. (7/1/2016)
In terms of the overall adjusted estimates of effectiveness for the two vaccines, overall 

effectiveness of LAIV4 was 46% with similar estimates for H1N1 A and B. Over 60% of isolates 

detected were H1N1, so there would not have been an overall statistically significant 

effectiveness if there was not a trend of effectiveness for H1N1. For IIV, the estimates were 

65%, 71% for H1N1, and 56% for B. With the greater sample size, the IIV estimates are much 

more precise. For children receiving any vaccine or at least one dose of vaccine, secondary 

analyses confirmed that the results are similar for those fully vaccinated, excluding those 

negative for any respiratory virus, and excluding those with high-risk conditions. The point 

estimates are all the same. When those with high-risk conditions are excluded, for LAIV the 

estimate of H1N1 VE is statistically significant.

Regarding overall VE for LAIV4 and IIV by calendar time, an interim analysis was performed at 

the end of February that showed an estimate of high effectiveness. As time went on and more 

subjects were enrolled and more cases were identified, the point estimate of VE decreased to 

46%. Waning immunity is a possibility, or it could just be gaining additional precision as more 

subjects are enrolled and more cases are identified.

 

Clearly, the ICICLE results differ from CDC’s results for LAIV. Supporting the ICICLE results is 

a 2015-2016 VE study by Public Health England (PHE). The PHE study is a test-negative VE 

study in UK children 2 through 17 years of age (N=279). 2015-2016 is the third year of the UK 

vaccination program. LAIV4 is the predominant vaccine used in UK children without 

contraindications. Vaccine uptake has been achieved in each of the three years of 

approximately 40%. The estimated overall LAIV4 VE was 57.6% (25.1, 76), which was 

statistically significant [Public Health England statement, June 22, 2016

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/530756/Influenza_vaccine

_effectiveness_in_primary_care_in_children.pdf]. The UK is aware of the data from the US and 

Finland, and is proceeding with their program for the upcoming season.

A 2015-16 VE study by the Finland National Institute for Health and Welfare (THL) was 

presented at the Nordic Vaccine Meeting in April 2016. This is a cohort study in Finland of 

58,857 children 24 through 35 months of age. They are using the comprehensive healthcare 

utilization and administrative databases that exist in Finland to comprehensively track outpatient 

visits, influenza positive tests, and vaccinations. Like the US and UK, the predominant A strains 

were H1N1. The overall unadjusted VE of LAIV was 46% (22, 63) and was statistically 

significant, and IIV was 60% (27, 78). Most of the cases were A strains, and the estimates were 

similar for LAIV at 48% and 78% for IIV.

 

The PI was consulted because these were unadjusted early estimates. However, the initial 

adjustments have been made and the estimates are very similar, changing by only a single 

percentage point and still being statistically significant. Finland routinely vaccinates children 6 

through 35 months of age, up to 60% of the LAIV recipients were previously vaccinated 

[Nohynek et al., Nordic Vaccine Meeting, April 2016. Confirmed by personal communication 

June 21, 2016]. The overall VE for all three studies is statistically significant with the estimates 

being 46% for US ICICLE, 58% PHE, and 46% Finland THL.

Based on data from recent seasons for LAIV and IIV across the different subtypes, highly 

variable results have been observed for H1N1pd09 for both vaccines, but especially for LAIV. 

In 2009, CDC described the high effectiveness of LAIV, albeit on a very small sample, and low 

effectiveness of IIV. In 2010-2011 with the trivalent formulation and 2013-2014 quadrivalent 

formulation, the reverse was observed in the CDC and ICICLE studies. Interestingly, in Canada 

This document has been archived for historical purposes. (7/1/2016)
in 2013-2014, there was high effectiveness of LAIV that was confirmed by a cluster randomized 

study conducted there in elementary school-aged children. Clearly, there have been highly 

variable results for the LAIV H1N1pdm09 strains. All of these studies were conducted with the 

A/California strain.

These variable results led to the investigations of the stability of that strain, which was found to 

be heat unstable. It was confirmed in the laboratory that real-world exposures that were 

confirmed to have occurred could negatively impact the potency of the vaccine upon 

administration. This led to the replacement of that strain with a more heat-stable H1N1pdm09 

LAIV strain, the A/Bolivia strain that was used in the 2015-2016 vaccines. In light of the recent 

data, there is clearly still a biological phenomenon that is reducing the effectiveness of the H1N1 

LAIV strains.

 

Significant research is underway to better understand the biology of the strains so that they can 

be further optimized in the future. For 2010-2013 VE of IIV and LAIV against Matched H3N2 in 

children, there was comparable effectiveness of LAIV and IIV with something of a trend toward 

higher effectiveness with LAIV perhaps. The 2010-2015 VE of IIV and LAIV against influenza B 

in children was very comparable.

Data from a CDC evaluation of seasonal effectiveness of LAIV and IIV in children 2 through 17 

years of age were summarized in a publication and are shown here:

Consistent with what Dr. Ambrose presented, the trend of favoring IIV for H1N1pdm09, but in 

some cases trending toward favoring LAIV for H3N2 and B [Chung et al, Pediatrics, 2015].

Any presentation of these studies requires a presentation of the limitations. There is a potential 

for bias in observational studies because the treatment is not being randomly assigned. Also, 

VE estimates can be imprecise and vulnerable to random effects. This is particularly true in this 

season where there is a small number of recipients in all of the studies (<150) in the CDC and 

ICICLE study, which makes it vulnerable to random effects. In addition to what is expected from 

This document has been archived for historical purposes. (7/1/2016)
cohort studies and others, multiple assumptions must be met to ensure study validity of the 

case-control approach. Those are well-summarized by Jackson et al in Vaccine. These are 

hard to check, but are the underlying assumptions for the framework of these studies providing 

valid estimates [Jackson et al., Vaccine. 2013].

In conclusion, three studies (four if the DoD study is included) demonstrated similar, statistically 

significant overall VE of LAIV4 in 2015-2016 in children 2 through 17 years of age of 46% to 

58%. These estimates are similar to VE observed with IIV in children in recent seasons1-3, 

although in the last season, lower effectiveness is being observed with LAIV compared to IIV. 

The differences from these four estimates compared to the CDC VE LAIV4 estimate may be 

due to limited sample, statistical power, and limitations of observational study design. 

MedImmune agrees that healthcare providers (HCP) should be made aware of these data so 

they can make informed decisions and have informed discussions with their patients in the 

upcoming season. AstraZeneca/MedImmune will share available 2015-2016 VE data with US 

HCPs to inform discussions of 2016-2017 vaccine options with patients. Research is underway 

to improve LAIV A/H1N1pdm09 strains in future seasons [1Ohmit et al, CID 2013; 2McLean et al, 

JID, 2014; 3Flannery B. ACIP presentation. December 2014].

LAIV Versus IIV Effectiveness: Summary of Evidence Since 2009

Dr. Brendan Flannery

Influenza Division

Centers for Disease Control and Prevention

As background for discussion, Dr. Flannery presented a brief review of LAIV and IIV 

effectiveness data in children and adults since 2009. To summarize the two presentations 

during this session for the 2015-2016 season: 

1) Data from the US Flu VE network indicate no LAIV effectiveness against A/H1N1pdm09 but

significant VE for IIV

2) Data from the US Department of Defense test-negative study indicate no LAIV effectiveness 

against A/H1N1pdm09 but significant VE for IIV

3) In a Medimmune presentation of data from the ICICLE test-negative study, the VE estimate 

against A/H1N1pdm09 was not significant despite a higher point estimate, but this study 

also identified significant VE for IIV. 

4) All studies reported higher VE for IIV than LAIV although point estimates varied

CDC received information from researchers from other countries where LAIV is used. All 

countries used quadrivalent LAIV this season. From a test-negative VE study in the UK, 

preliminary data indicate significant adjusted VE for LAIV against any influenza A or B among 

children 2 through 17 years of age. A national observational cohort study conducted in Finland 

reported significant unadjusted estimates of LAIV effectiveness against influenza A, mainly 

H1N1pdm09, among 2-year olds. Point estimates were higher for IIV, but confidence intervals 

overlapped. There was no estimate of LAIV effectiveness in children from the Canadian testnegative study this season, nor was there an estimate from Israel where LAIV was not available 

this season. 

This document has been archived for historical purposes. (7/1/2016)
For each of the last three seasons, the US Flu VE Network has identified no significant 

effectiveness of LAIV against medically attended influenza. In two of these seasons, the 

predominant influenza virus was A/H1N1pdm09 and in one season, antigenically drifted A/H3N2 

viruses predominated. In the first three seasons, LAIV was trivalent. Quadrivalent LAIV 

replaced LAIV3 in 2013-2014. It was not possible to separate any effects of quadrivalent 

vaccine during the last three seasons from factors related to the circulating viruses during those 

seasons. In the US Flu VE network, three seasons since 2009 had enough A/H1N1pdm09 

circulation to estimate LAIV and IIV effectiveness. None of the estimates for LAIV were 

significant, and relative effectiveness significantly favored IIV in all three of these seasons. In 

three seasons since 2009, LAIV and IIV showed similar effectiveness against influenza A/H3N2, 

and in 2014-2015, as previously mentioned, neither LAIV nor IIV provided significant protection 

against the predominantly drifted H3N2 viruses. Against influenza B viruses, estimates of LAIV 

and IIV effectiveness were similar during three seasons since 2009. For the 2015-2016 season, 

the estimate for LAIV effectiveness against influenza B viruses was not statistically significant, 

while significant effectiveness was found for IIV. The relative effectiveness analysis did not find 

a significant difference between IIV and LAIV against influenza B viruses in 2015-2016.

For the 2013-2014 season, all LAIV in the US was quadrivalent and all LAIV outside the US was 

trivalent. There were three observational VE studies conducted in the US during 2013-2014: 

US Flu VE study, MedImmune’s ICICLE post-marketing study, and the DoD-led study among 

military dependents. None of the three studies identified significant VE for quadrivalent LAIV 

against the predominant H1N1pdm09 virus, while all found significant VE for trivalent inactivated 

vaccine against H1N1pdm09. These data led to a change in the LAIV H1N1pdm09 HA 

component from A/California to A/Bolivia. The 2015-2016 season is the first season in which 

LAIV contains the updated H1N1pdm09 construct. Finally, there was one CDC-funded 

household cohort study conducted by the University of Michigan that found a high point estimate 

of 82% for LAIV effectiveness, but did not find significant VE for either LAIV or IIV due to small 

numbers of influenza cases in the cohort. 

During 2013-2014, CDC began conducting a relative effectiveness analysis of US Flu VE data

as part of the GRADE consideration for the preferential recommendation of LAIV. The analysis 

is modeled after the LAIV-IIV comparative efficacy studies conducted before 2009, comparing 

odds of influenza in vaccinated children. Relative effectiveness against H1N1pdm09 

significantly favored IIV in two seasons, 2010-2011 and 2013-2014. There were no significant 

differences in LAIV versus IIV against A/H3N2 or B viruses in the seasons indicated.

During 2013-2014, several studies of trivalent LAIV were conducted outside of the US. Two 

observational studies conducted outside the US during the 2013-2014 seasons, one in the UK, 

and one in Canada, did not find statistically significant effectiveness of trivalent LAIV despite 

high point estimates in the observational VE study in Canada. Of note, although the UK study 

did not find effectiveness for trivalent LAIV against the A/H1N1pdm09 virus, an ecologic 

analysis observed a trend toward reduced influenza incidence in LAIV pilot areas in which about 

50% of school children in the target age range received LAIV. In addition, in a clusterrandomized trial of trivalent LAIV compared to trivalent IIV, influenza incidence was significantly 

lower in LAIV vaccinated students and their contacts compared to students vaccinated with IIV 

and their contacts during the 2013-2014 season when H1N1pdm09 predominated.

This document has been archived for historical purposes. (7/1/2016)
In terms of data comparing LAIV and IIV effectiveness in adults from the DoD Global 

Laboratory-based Influenza Surveillance System, these data are from published estimates of 

LAIV and IIV effectiveness among active military aged 18 years and older for 2010-2011 

through 2013-2014. Estimates for 2011-2012 include dependents and children. The VE 

estimates are from test-negative studies using the laboratory-based surveillance system, and 

are against all influenza types A or B. Nonsignificant estimates were reported for LAIV 

effectiveness against any influenza in the 2010-2011 and 2013-2014 seasons, and for IIV in 

2013-2014. Adjusted estimates were similar for LAIV and IIV during 2011-2012 and 2012-2013 

[Eick-Cost 2012; MacIntosh 2013; Eick-Cost 2013; Cost 2014].

Finally, there are limited data on the serologic response to the A/H1N1pdm09 LAIV vaccine 

component or shedding of vaccine virus. One small Norwegian study of 38 children vaccinated 

with trivalent LAIV showed reduced antibody response measured by HI titer increase to the 

H1N1pdm09 component compared to H3N2. Serologic studies by US Flu VE network sites 

have shown limited increase in H1N1pdm09 titers following quadrivalent LAIV vaccination even 

among children with low pre-vaccine baseline HI titers. Another small study demonstrated that 

shedding of A/H1N1pdm09 vaccine virus following LAIV was reduced after repeat LAIV 

vaccination, but found no influence of pre-vaccination serum antibody titer on H1N1 vaccine 

virus shedding. Unfortunately, serologic and viral shedding data may provide little information to 

identify problems with the A/H1N1pdm09 vaccine component without a better understanding of 

correlates of protection for LAIV [1 Mohn, JID 2014; 2US Flu VE network (unpublished); 

3Ilyushina, JID 2014].

To summarize the available data for LAIV effectiveness since 2009, preliminary US Flu VE 

Network data for 2015-2016 indicated that quadrivalent LAIV offered no significant protection 

against influenza A (H1N1)pdm09 in children aged 2 through 17. Poor VE for quadrivalent LAIV 

was observed during two preceding flu seasons in children aged 2 through 17: 





2013-2014: No significant VE for LAIV4 against A(H1N1)pdm09

2014-2015: No significant VE for LAIV4 or IIV3/4 against drifted A(H3N2) viruses

During previous seasons, most evidence demonstrated that LAIV3 worked as well as IIV3 

against A(H3N2) and B viruses in children aged 2 through 17. There was poor VE for LAIV3/4 

against A(H1N1)pdm09 in active military. 

The reason for poorer overall performance of LAIV compared to IIV, particularly with regard to 

the A(H1N1)pdm09, over the last few seasons is not well-understood and is a subject for further 

study. How well the influenza vaccine works can vary by season, virus type/subtype, the 

vaccine, and age and other host factors of the people being vaccinated. While the causes of 

the low estimate of 2015-2016 VE in the US VE Network studies are not clear, some 

possibilities include:







Suboptimal performance of the A/Bolivia/559/2013 (H1N1) HA vaccine strain.

Potential interference among viruses in the quadrivalent vaccine [i.e., additional B 

vaccine component effects viral replication of A(H1N1)pdm09 virus].

Reduced immunogenicity of LAIV (or replication in nasal passages?) resulting from a 

more highly vaccinated population in recent years; compared with populations of earlier 

studies, in which it is likely that a higher proportion of children were vaccine-naïve.

This document has been archived for historical purposes. (7/1/2016)
Discussion Points

Dr. Stanley Plotkin (Audience Member) noted that while they had heard a great deal of 

epidemiologic data, what struck him was the lack of immunologic data. LAIV is more 

complicated than IIV in the sense that one needs to assess serum responses intranasal, IgA 

secretory responses, and even cellular responses that have all been associated as correlates of 

protection. He asked whether there were any data on the recent vaccine.

Dr. Ambrose replied that he was not aware of any data on the 2015-2016 vaccine, including the 

A/Bolivia strain, in terms of cellular or antibody responses. As Dr. Flannery summarized, there 

are studies with the A/California H1N1pdm09 strain and a few others that generally show that 

there is shedding, antibody responses, or T-cell responses. But, they are lower than what is 

generally seen for other strains. It is very difficult with IIV to pinpoint an exact correlate. It is 

consistent with the more moderate effectiveness in that the responses are more in the moderate 

range.

Dr. Karron thought it had been quite challenging to find a correlate of protection for LAIV, and it 

is not for lack of looking. In many of the studies, there was a lot of effort to look at correlates of 

protection. In fact, vaccine shedding is probably a better correlate. She wondered what data 

exist, if any, about the relative shedding of various components. Regarding licensure of LAIV 

and related to Dr. Plotkin’s question, at the time it was licensed it was based on immunogenicity 

equivalents. But, the serum antibody responses to the trivalent and the quadrivalent vaccine 

were very modest. At that time, the FDA specifically called for effectiveness studies to look at 

this issue of effectiveness of the quadrivalent preparation. Given these data about 

effectiveness, she wondered what the FDA’s plans were.

Regarding shedding, Dr. Ambrose said that when they reviewed the comprehensive data 

following the 2013-2014 data, it was mixed. One study of the trivalent formulation showed 

relatively high shedding of the H1N1pdm09 A/California strain close to 60%. In a subsequent 

quadrivalent study, it was lower in the 10% to 20% range. Frustrating about that study was that 

the first sample was on Day 4 to 7 post-vaccination, which is after the peak shedding would 

occur.

Dr. Sun (FDA) said that the data are obviously of concern to the FDA. FDA has been working 

with CDC and MedImmune since the 2013-2014 findings. They also recognize that influenza is 

a very complex disease and that there are occasional surprises. The FDA always approaches 

these types of matters with deliberateness, especially given the fact that all of the study results 

have not been fully reviewed. He thought it was fair to say that the studies are not completely 

consistent. It is also important to recognize that the LAIV approach has offered advantages in 

the past for influenza over IIV, especially among certain age groups. LAIV continues to be an 

important alternative in the armamentarium against influenza. As part of the evolutionary 

process, changes have been made in order to try to address this problem. Obviously, more 

work needs to be done. There are additional studies that FDA would like to see from 

MedImmune and others. At this point, FDA is not ready to undertake a requirement for 

changing the prescriber’s information. FDA wants to continue to work with MedImmune to find 

out the root cause of this phenomenon. They are also engaged in internal discussions about 

what else can be done.

This document has been archived for historical purposes. (7/1/2016)
Dr. Harriman noted that the ICICLE study was in US children while the UK and Finland studies 

were in different populations. She wondered if there was any thought that those two are more 

likely to be influenza vaccine naïve.

Dr. Flannery responded that the ICICLE, MedImmune, and US Flu VE studies, the percentages 

of previous vaccination are very similar as would be expected in the US population at between 

70% and 80%. They do not have the actual numbers from the UK and Finland. The sense is 

that the UK has had uptake in several years of a pilot program that has been expanded, so 

there has been relatively less exposure in that population. In the Finnish study, about 60% of 

the children have received vaccine. Finland does not have a universal infant vaccination 

program, so the LAIV and IIV program beginning in 2 year olds, a lot of those children are 

receiving vaccines early on in the schedule, but this is the beginning of their vaccination 

program. For that cohort, if they were 2 year olds and received prior vaccination, they would not 

have been expected to see more than just that one prior vaccination.

Dr. Bresee (SME) asked whether Dr. Ambrose knew what the VE against the H1 strain 

specifically is.

Dr. Ambrose responded that in the Finland study, the predominant strains were A strains and 

H1N1 strains. This is where there was 47% for LAIV that was statistically significant, and 78% 

for IIV that was statistically significant. In the UK program, he had only the overall vaccine 

effectiveness. His understanding was that their epidemiology last year was very similar to the 

US in which the predominant strain was H1N1 and they had B/Victoria strain circulating as well.

Dr. Gorman (NIH) asked whether the study in Canada was conducted on naïve children or if 

children had been previously vaccinated with LAIV.

Dr. Flannery responded that there was a very low vaccination rate in that cohort, so they 

conducted a trial. 2013-2014 was the second season, so some children were vaccinated over 

the two seasons. In one group, it is school vaccinations.

Dr. Romero noted that the Influenza VE Net and ICICLE studies had overlapping centers: 

Marshfield and Baylor Scott & White. The two sites in the ICICLE study account for one quarter 

of the sites, while Flu VE Net is one third of the sites. He wondered whether any comparison 

had been done of the VE at both of these sites, and if the analyses for the differences in VE 

hold up when that group alone was assessed.

Dr. Ambrose responded that for the two sites in the ICICLE study, the estimates of VE were 

very similar, almost identical, to the overall vaccine effectiveness observed in the entire study. 

Dr. Flannery indicated that there was an extra slide, 33, in the slide set that may be helpful in 

terms of answering the questions related to what the differences are in the studies and at the 

sites. The two sites contributed LAIV-vaccinated children, but they did not have a large number. 

CDC’s data for those two sites are very similar to the MedImmune data overall. The other sites 

contributed LAIV vaccinated children as well as H1N1 cases or failures in LAIV children. There 

were about 150 total LAIV recipients versus about 753 children enrolled who had received 

inactivated vaccine. CDC is not comfortable breaking down the LAIV data by site. There is 

some site-to-site variability, but CDC sees the overall estimate as a reflection of the whole. 

There are more similarities than differences in the two studies. An effect modification has not 

been observed of prior season vaccination. There is no explanation for prior vaccine as an 

This document has been archived for historical purposes. (7/1/2016)
effect modifier of what is seen as low VE for LAIV. The MedImmune study enrolls children with 

an ILI definition of fever specifically. Overall estimates do not change when children are 

restricted to those who have cough and fever and / or sore throat. If patients are restricted who 

are enrolled within 5 days of illness onset, very similar estimates are observed.

Dr. Kempe noted that there was a percentage that relied on report, which might differ between 

getting a shot or inhaled vaccine. She heard that in the CDC presentation not the others. She 

asked what percent that was and if that issued had been studied.

Dr. Flannery responded that about two thirds of their children are two to eight year olds, all of 

which is by document. There is no self-report. For a small number of children, there was 

parent-report of vaccination that was outside of the health system that provided the documents. 

So, it is plausible because they were able to provide a location outside the system and a date, 

but that really is a small number of children. If the analysis is limited to documented vaccination 

only for both of those age groups, the overall estimates are still the same for LAIV and IIV.

Proposed Recommendations Summary / Vote 

Lisa Grohskopf, MD

Influenza Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Grohskopf reminded everyone that what was discussed and approved during the February 

2016 meeting was reiteration of the core recommendations that annual influenza vaccination is 

recommended for all persons 6 months of age and older. There was a minor change in timing 

of vaccination language and changes to the egg allergy recommendations allowing use of LAIV 

and removing the 30-minute post-vaccination waiting period that had been recommended 

previously. There was also some additional specific language about the specific case of 

individuals with a history of severe egg allergy.

New Licensures that that will be listed in the Available Products table include: 1) Fluad®, the 

MF59-adjuvanted inactivated influenza vaccine trivalent from SeqirusTM, which is for persons 65 

years of age and older; and 2) Flucelvax Quadrivalent®, which is the cell-culture-based 

inactivated influenza vaccine, which has been available previously as trivalent and now will be 

available as quadrivalent for persons years of age and older. ACIP has had the opportunity to 

hear presentations on these. Potential upcoming licensures, which also have been presented at 

ACIP, which will not be in the table as they are not yet licensed, but will be acceptable options to 

existing products for appropriate age groups if licensed: 1) Flublok Quadrivalent®, which is a 

recombinant quadrivalent influenza vaccine for persons 18 years of age and older; and 2) 

Flulaval Quadrivalent®, which is an inactivated influenza vaccine for persons 6 months of age 

and older. Again, those will not be in the table but will be mentioned as potential upcoming 

licensures and will be viable options for existing products in the relevant age groups once 

licensed.

In terms of LAIV efficacy, the WG had the opportunity to hear presentations of the data heard 

during this session and an opportunity to discuss it. One of the considerations that went into the 

discussion was the importance of ensuring that policy reflects understanding of the latest VE 

data, which in this case indicates that at least in the US data, IIV is more effective than LAIV

against influenza A(H1N1)pdm09, which was the predominant circulating virus this year. There 

This document has been archived for historical purposes. (7/1/2016)
is also an understanding that there is an uncertainty about LAIV4 effectiveness against A(H3N2) 

and B viruses, which has been available since the 2013-2014 season. Most notably, there has 

not yet been an opportunity to see how well the quadrivalent performs against A(H3N2) in a 

season where there is good match. 2014-2015 was an H3N2 predominant season, but there 

was drift of H3, so there was poor match and the inactivated vaccine did not perform well either. 

There is a conviction that policy should encourage use of the most effective vaccines available, 

and a conclusion in general that LAIV should not be used in routine practice though there was 

not consensus regarding the exact language surrounding that. There was also discussion that 

there is a need to specify that changes in the recommendations are interim, if there are 

changes, for the 2016-2017 season, as data may be different in future seasons. 

There was discussion of a number of programmatic implications should the recommendations 

change. There was a lot of discussion regarding the potential impact on vaccine supply if LAIV 

is not recommended for use. It is projected that there should be a maximum produced 171 to 

176 million total maximum doses projected for all influenza vaccines. This information was 

presented at the Adult Influenza Vaccination Summit in May. Among these doses, about 14 

million are projected LAIV doses, which is about 8% of the total. There was recognition that 

providers may have difficulty purchasing other products and also understanding of the fact that 

not all products are licensed for all age groups. There are other vaccines, inactivated and 

otherwise, which are not licensed for children for example. CDC has contacted manufacturers 

regarding the likelihood of mitigating any potential shortages. A second concern raised was that 

this may impact school-based programs, many of which primarily use LAIV. One recent 

publication indicates that this is not a large number of children. In recent seasons, an estimated 

5% of children were vaccinated at school, 55% of whom received LAIV according to that study.

If LAIV were not to be used, there would be no alternative for those who refuse injectable 

vaccine if LAIV is not recommended for use. This may impact vaccine coverage. 

Communicating to providers and parents the rationale for the policy change was felt to be 

critical to maintaining a strong influenza vaccine program. There was also concern that any 

change in the LAIV recommendations may potentially result in decreasing LAIV use, which may

in turn preclude evaluation of LAIV effectiveness in future seasons because there will not be the 

same numbers witnessed in recent seasons. With that in mind, two basic options were raised: 

Option A: 















LAIV should not be used in any setting

More definitive response to the available data

May be more clear to communicate message

Option B:

LAIV may be used in settings where otherwise an individual may not be 

vaccinated

Leaves flexibility in the program for certain situations

Iterative step, may be easier to transition back to LAIV if the vaccine is 

reformulated

May limit the programmatic impact of change

This document has been archived for historical purposes. (7/1/2016)
The potential language posed for each option follows:

Option A: Interim Recommendation That LAIV Should Not Be Used

“In light of the evidence for poor effectiveness of LAIV in the U.S. over the last three 

influenza seasons (2013-14 through 2015-16), for the 2016-17 season, ACIP makes the 

interim recommendation that LAIV should not be used.”

Option B: Interim Recommendation for Limited Use of LAIV

“In light of the evidence for poor effectiveness of LAIV in the U.S. over the last three 

influenza seasons (2013-14 through 2015-16), for the 2016-17 season, ACIP makes the 

interim recommendation that LAIV should not be routinely used. Use of LAIV may be 

considered in certain circumstances.”

Examples may include (clinical guidance to be developed by CDC): 







Refusal of injectable vaccine

Shortage of age-appropriate IIV or RIV

School based programs with no alternative vaccine

Discussion Points

Regarding the WG’s thoughts about this information, Dr. Karron indicated that this was very 

much a rapidly evolving situation so some of the language shown differed from what the WG 

saw. In the initial discussion with the WG, there was also the option of not making any change 

to the recommendation, for which there was no enthusiasm. The WG was very clear that some 

change was needed. There was division as to whether it should be a recommendation that 

LAIV should not be used, or should be used under certain circumstances. For those who felt 

that perhaps it should be used under certain circumstances, most of the concerns were 

programmatic in nature and related to implementation.

Dr. Moore pointed out that the way the language was written, it implied that LAIV was 

particularly bad for the last three seasons. Given that no formulations had good effectiveness in 

the 2014-2015 season, it might be fairer to state something to reflect that the problems were 

different during that season and that it was not the fault of any vaccines.

Dr. Reingold asked whether the current statement was preferential for IIV and if not, whether 

any consideration had been given to a statement that would state a preference for IIV.

Dr. Karron replied that the existing statement has no preference for one over the other. The 

statement considered in the WG regarded stating a preference for IIV. She invited the WG to 

comment. The original statement the WG considered was a reverse preferential 

recommendation in favor of IIV, but the WG was divided on this.

Ms. Pellegrini requested further information regarding why the full membership was seeing such 

different recommendations from the ones the WG originally considered as the IIV preference.

This document has been archived for historical purposes. (7/1/2016)
Dr. Bresee (SME) said he thought what the WG was commenting on demonstration of data that 

indicated a lack of effectiveness of one of the choices, so the word “preference” seemed to 

connote the difference between a good vaccine and a better vaccine. The wording that it had 

“limited use” seemed more aligned with what the data are showing.

Dr. Kimberlin (AAP) extended gratitude to the Influenza WG and to MedImmune for responding 

quickly to a rapid developing and changing sequence. This has a major impact on pediatric 

practices. A number of emergency calls have been conducted that assessed the pediatric 

practice equivalence of programmatic changes and impacts. However, everything kept circling 

back to the science for the AAP. The science simply shows that one product has not worked for 

the last three years; whereas, IIV has. Thus, AAP prefers Option A for that reason.

Dr. Savoy (AAFP) pointed out that many people have likely ordered their vaccine for the 

upcoming year, and it is probably too late to change that. If she were to see this 

recommendation, she would want to know explicitly whether ACIP was telling her not to give 

that vaccine or that she should give it but should know that it might not work as well. People are 

going to need to make some practical decisions about this.

Dr. Wharton responded that this would depend upon what ACIP recommended as well as the 

clinical guidance developed subsequently. If language like Option B were used, she thought it 

would suggest that if some amount of LAIV had been purchased, it might be appropriate to use 

in limited circumstances but not the way it was used last year. Regarding the issue of supply, 

the manufacturers could make statements about what vaccine remained available. However, 

even if all the numbers were reassuring, there still is likely to be some difficulty for individual 

providers if they did need to obtain influenza vaccine to identify vaccines that might be ageappropriate for their patients. This might require a higher level of efforts, and all providers may 

not be prepared to do this. The end result is that some providers might not end up with 

influenza vaccine for their patients.

Dr. Gorman (NIH) asked whether the determination regarding the poor effectiveness was driven 

primarily by the A strains and the H1N1 strains.

Dr. Karron said she thought the data were clear for H1N1 and the data for other strains were 

less clear, but concerning. Certainly, there was poor effectiveness of the vaccine last year with 

a mismatched year. In prior years with H3N2 and mismatching, there has been variation in 

efficacy or effectiveness. She wondered if they had ever seen zero or negative even if there 

was a very bad mismatch. That certainly was a concern in the WG.

Dr. Ambrose showed the following graphic of the three observational, test-negative studies 

conducted in 2014-2015 for LAIV4 and IIV. The CDC study on the left efficacy was 17% for IIV 

and -8% for LAIV4. The ICICLE study was 40% for IIV that was significant, and 30% for LAIV4 

that was not significant. The UK PHE results were very similar. The additional data available 

were from a randomized placebo controlled study conducted in Japan in children 7 through 18 

years of age. Many of these children were previously vaccinated with inactivated vaccine. In 

that study, efficacy was 23% against completely mismatched strains and that was statistically 

significant; whereas, in the UK and US observational studies some matched strains were 

circulating. There was evidence that LAIV was working, albeit at a low level against those 

mismatched strains, which was not detected by the CDC study but would be consistent with 

what was observed in the ICICLE and UK PHE study. In terms of how this relates to past data, 

in the original Belshe study in 1997-1998 demonstrated 86% against mismatched strains. 

This document has been archived for historical purposes. (7/1/2016)
According to CDC classification, those were four-fold different. Similar high relative efficacy was 

seen compared to inactivated vaccine when there were four- to eight-fold different viruses in 

2004-2005. But there was an 8- to 16-fold difference in 2014-2015, the absolute efficacy 

estimates were in the 20% to 30% range. Essentially, the randomized trial and much of the 

observational data, at least from ICICLE and PHE, were consistent with what has been 

observed before with the trivalent formulation against severely mismatched by a 16-fold 

difference in H3N2. Statements being made that no effectiveness is demonstrated are not 

correct. This is the classic “absence of evidence is not evidence of absence.” There is no 

evidence of zero percent effectiveness of LAIV. There is just evidence of low effectiveness that 

is not significant.

Dr. Messonnier thanked the ACIP membership, recognizing the complexity of this discussion. 

As everyone must have gathered, Dr. Frieden saw these data before joining them earlier in the 

morning. He tried to focus on the need to make decisions based on imperfect data. As a 

science-driven group, ACIP must make a decision about whether they have actionable data. 

Her understanding from the WG deliberations was that despite the fact that there are 

discrepancies in the data, the WG felt strongly that these data are actionable. Where they fell 

out of consensus regarded whether it was absolute that the vaccine should not be used, as AAP 

supports, or whether because of some of the programmatic issues, which AAFP pointed out, 

there should be some space such that if clinicians had no other option, it would be better to give 

LAIV versus nothing. She asked the group to deliberate these issues, remember that someone 

ultimately will have to offer clinical guidance to individuals, clinicians, and parents faced with this 

decision.

Dr. Lett (CSTE) thought it would be helpful to know more about how binding pre-books would be 

in the private and public sectors.

Dr. Wharton responded that on the public sector side, CDC would take their cue from and would 

implement what ACIP advised. In terms of the private sector, individual providers are likely to 

have various purchase agreements which they would have to deal with themselves.

As a member of the WG, Dr. Zahn (NACCHO) commented that for Option B, the discussion was 

that LAIV would be given if the option of IIV was not available. While he appreciated Dr. 

Bresee’s point that they did not want it to appear preferential, having multiple bullet points about 

various situations felt more preferential than simply stating to give IIV unless there was no other 

This document has been archived for historical purposes. (7/1/2016)
choice as a provider than to give LAIV. There was some conversation among the WG members 

about avoiding saying too much to providers, because providers have many other issues with 

which they must deal.

Dr. Bennett said she thought the changing in wording from the use of the word “preference” to 

the use of “should not be routinely used” and “may be considered in certain circumstances” 

addressed what Dr. Zahn was saying.

 

Dr. Moore said that as an Immunization Manager and member of the committee, what struck 

her as important pertained to who H1N1 disproportionately affects with more severe disease. 

Younger adults and children tend to have more severe disease with H1N1, which also happens 

to be the group for whom LAIV is targeted. Knowing that it will not work against H1N1 or that 

there is no evidence of effectiveness, she would not feel comfortable giving a child that vaccine 

because if it is an H1N1 year, it would leave them vulnerable. Programmatically, LAIV 

comprises 8% of the total supply available. This can be figured out. However, she worried also 

about sending the message that whomever receives LAIV has gotten an inferior product. That 

has another layer of communication complications. The public looks to ACIP to make 

recommendations for the best possible vaccines.

Not being a member of the WG, Ms. Pellegrini found this to be a lot of information to absorb on 

short notice and about which to make a very important decision. She said she was struggling 

with the differences in effectiveness data among the strains, and among the strains from yearto-year. She found the difference among the results in different countries to be particularly 

confounding. She wondered what it was about the US that the vaccine did not work, while the 

same vaccine seemed to work in other places. Setting aside 2014-2015 as a season of 

mismatch, they were looking at two different vaccines because the A strains were California and 

Bolivia. It is still H1N1, but is a slightly different vaccine. Also setting aside 2014-2015, she felt 

like there were two data points. A couple of years ago, ACIP preferentially recommended LAIV 

based on one really strong data point and they regretted that. She was not much happier 

dealing with what felt like to her to be two data points to make the opposite recommendation. 

On the basis of all of this, she said she would like the committee to consider postponing a vote 

until the next morning to give the members time to review and process the information.

Dr. Karron said she felt Ms. Pellegrini’s pain in terms of the data. She clarified that the GRADE 

analysis performed for a preferential recommendation of LAIV was not based on a single data 

point. It was based on several RCTs. Unfortunately, those were for a different vaccine 

essentially—the trivalent vaccine. She found the fact that the H1N1 components had been 

changed but the results were the same to be especially disturbing and concerning in terms of 

the efficacy of this vaccine against H1N1. There may be issues of viral interference. There may 

be issues connected to the fact that the US has a more highly immunized pediatric population 

against influenza than anywhere else in the world, which may contribute to differences observed 

in the US versus other populations. Less is known about H3N2 and B, but she thought that the 

data for H1N1 were quite compelling.

Dr. Messonnier acknowledged that ACIP was being rushed. Unfortunately, CDC felt a great 

sense of urgency to make some sort of recommendation. Putting it off until the morning might 

mean that other things could not proceed. No decision would basically be a decision, so no 

vote would not be helpful.

This document has been archived for historical purposes. (7/1/2016)
Echoing Dr. Karron and responding to Dr. Messonnier, Dr. Schaffner (NFID) suggested that this 

issue should not depend at all on programmatic issues. ACIP should decide whether LAIV is an 

ineffective or insufficiently effective vaccine. If that was the decision, Option A was clear. He 

suggested that Option A was the clear choice.

Dr. Baker (IDSA) thought this was great because CDC is filled with very capable people who 

can interpret data without an advisory committee. However, this is why CDC has an ACIP. She 

appreciated Dr. Messonnier bringing them back to Dr. Frieden’s comment. Things change. The 

one thing she has learned about influenza is that it changes all of the time—the virus, the policy, 

et cetera. She thought that the science made this actionable, and that they did not have a 

choice. She said she had great sympathy for doing something with Option B in terms of all of 

the programmatic issues, but the science suggested that Option A was correct. She was not 

sure whether overnight would be helpful, but she thought a decision must be made.

Dr. O’Leary (PIDS) indicated that the Pediatric Infectious Disease Society (PIDS) would like to 

support Option A for many of the reasons articulated. Moreover, there are good data to show 

that IIV is effective though it varies from year-to-year. However, there were enough 

unanswered questions about LAIV that he did not think they could recommend in good 

conscience its use in children.

Dr. Gorman (NIH) pointed out that if Option A was approved and the recommendation went to 

Dr. Frieden and he agreed, he wondered whether insurances would be freed of their 

responsibility of paying if providers administered an FDA-approved vaccine to those children.

Dr. Bennett requested input from Dr. Wharton, pointing out that this was also why the VFC vote 

had been tabled. There are a number of financial implications that must be better understood.

Dr. Wharton responded that it is difficult to predict what exactly insurers would do. In general, it 

is not expected that insurance coverage would change immediately following an ACIP 

recommendation. Generally changes are phased in over time.

Dr. Bennett added that it usually takes a year from the time ACIP makes a recommendation.

Having been a private practitioner for 20 years, Dr. Gorman (NIH) noted that it took a year to 

start paying. He did not think it would take a year to stop paying. 

Vote: Influenza Vaccine Recommendations

Dr. Harrison motioned to approve Option A. Dr. Walter seconded the motion. The motion 

carried with 13 affirmative votes, 1 negative vote, and 1 abstention. The disposition of the vote 

was as follows:

13 Favored: Bennett, Ezeanolue, Harriman, Harrison, Karron, Kempe, Moore, Romero, 

Reingold, Riley, Rubin, Stephens, Walter

 1 Opposed: Pellegrini (due to insufficient time to review the data)

 1 Abstained: Belongia (due to conflict of interest)

Although they voted “yes,” many ACIP members expressed regret. Dr. Bennett lamented that it 

was a very sad day for the influenza vaccination program. However, she stressed that “if you’ve 

This document has been archived for historical purposes. (7/1/2016)
seen one influenza year, you’ve seen one influenza year” and that they might be back next year 

reaching a very different conclusion.

VFC Vote: Influenza Recommendation

Dr. Jeanne M. Santoli

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Santoli indicated that the purpose of this resolution was to update the resolution to remove 

LAIV from the VFC program. No changes were proposed to the IIV component of the 

resolution.

The other sections of this component of VFC resolution will not be changed. The following 

statement will be included regarding updates based on published documents:

If an ACIP recommendation regarding influenza vaccination is published within 6 months 

following this resolution, the relevant language above (except in the eligible groups 

sections) will be replaced with the language in the recommendation and incorporated by 

reference to the URL.

Discussion Points

Dr. Thompson requested clarification regarding the implications of approving this resolution in 

terms of payment for physicians for VFC-ordered vaccines if they have already ordered / paid 

for them. She also asked for clarification of the implications of the timing of the resolution in 

terms of current influenza season vaccinations.

Dr. Santoli responded that providers receive VFC vaccines at no charge. CDC provides 

contracts and makes doses available to states for the VFC program. This indicates that CDC 

will make vaccines available for children who are covered by the VFC program, and those are 

the vaccines to which providers of the VFC program will have access and will be able to 

administer. They do not bill for these vaccines, although they do bill for the administration fee. 

That will occur as normal, but the resolution will limit the formulary for influenza vaccines that 

CDC will make available through the VFC program this year. 

Vote: VFC Influenza Vaccine Recommendation

Dr. Kempe motioned to approve the VFC Influenza Vaccine Recommendation. Dr. Rubin 

seconded the motion. The motion carried with 13 affirmative votes, 1 negative vote, and 1 

abstention. The disposition of the vote was as follows:

13 Favored: Bennett, Ezeanolue, Harriman, Harrison, Karron, Kempe, Moore, Romero, 

Reingold, Riley, Rubin, Stephens, Walter

 1 Opposed: Pellegrini (due to insufficient time to review the data)

 1 Abstained: Belongia (due to conflict of interest)

 

This document has been archived for historical purposes. (7/1/2016)
No public comments were offered during this session.

Introduction

Ruth Karron, MD

Chair, Respiratory Syncytial Virus Vaccine Work Group

Dr. Karron said that she was delighted to introduce the Respiratory Syncytial Virus (RSV) WG, 

both because RSV is such an important pathogen in young children and the elderly and also 

because so much has been accomplished in terms of vaccine development; therefore, it is time 

to constitute an ACIP WG.

RSV was discovered almost 60 years ago in 1957. It is a major cause of lower respiratory tract 

illness (LRTI) in infants, young children, and older adults. In the US, there are approximately 

150,000 hospitalizations each year in US infants and children and approximately 180,000 

hospitalizations in US elderly. In the US, these represent the “tip of the iceberg,” and there is a 

substantial outpatient disease burden in both populations. RSV is a global pathogen and it is a 

leading cause of hospitalization and serious LRTI in children throughout the world. Despite 

having been recognized as a human pathogen 59 years ago, a vaccine does not exist. There is 

a monoclonal antibody (mAb) called palivizumab, but that is given as a monthly injection, is 

quite expensive, and is recommended for only a subset of high-risk infants. 

The following graphic represents the RSV vaccine landscape in 2003, with just a couple of 

companies and NIH involved in developing vaccines:

Day 1: Public Comment

Respiratory Syncytial Virus Vaccine 

This document has been archived for historical purposes. (7/1/2016)
Contrast that with the current state of affairs shown in the following graphic of 2016 mAb and 

RSV vaccine development:

There are approximately 60 products in development, of which 3 are in Phase 3 development. 

Two of the vaccines in Phase 3 development are manufactured by Novavax. One is currently 

being evaluated in mothers for maternal immunization to protect young infants, and one has 

completed enrollment in the elderly. There are a number of other products, but the products in 

particular that are meant for the elderly are further along in clinical development than the 

products meant to protect young children, either through maternal immunization or through 

active immunization of the infant.

For that reason, at this time, the WG was constituted to focus primarily on the elderly because it 

is anticipated that a vaccine could be licensed as early as 2017-2018. The current terms of 

reference for this WG are to consider recommendations for the use of RSV vaccine in adults 60 

This document has been archived for historical purposes. (7/1/2016)
years of age and older and in adults with underlying medical conditions. The current tasks of 

the WG are to:









Review the epidemiology of RSV infection and burden of RSV disease in older adults;

Review efficacy, immunogenicity, safety, and cost-effectiveness of RSV vaccine(s) in older 

adults and adults with underlying medical conditions as these data become available;

Provide evidence-based recommendations regarding use of RSV vaccine(s) in older adults; 

and

Identify areas in need of further research for informing potential future vaccine 

recommendations.

Because it is anticipated that over time, there also will be vaccines to consider for protection of 

infants and children, the terms of reference and the membership of the WG may evolve over 

time to accommodate these additional needs. With the exception of the liaison members, the 

WG initially was constituted with the focus on elderly adults in mind.

This session included an overview of RSV and RSV vaccines with regard to obstacles and 

progress in RSV vaccine development, targeted vaccine populations, and considerations for 

RSV vaccine use. Future presentations will include presentations on burden of RSV in older 

adults, clinical trial results, and cost-effectiveness. 

 

Overview of RSV Vaccines

Lindsay Kim, MD, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Kim began by acknowledging Dr. Karron’s mentorship and leadership in the standing up of 

this ACIP WG. She explained that RSV is a common cause of acute respiratory infections (ARI) 

in infants and young children. By the first year of life, 50% are infected, with virtually all children 

infected with RSV by 2 years of age. RSV is the most common cause of LRTI among infants, 

and it frequently manifests as bronchiolitis or pneumonia. It can present with apnea in infants 

less than 6 weeks of age. There is a questionable relationship between RSV infection during 

early childhood and subsequent development of reactive airway disease and wheezing.

In adults, RSV can cause repeat infections after being exposed and infected during infancy and

early childhood. It most often causes upper respiratory tract illnesses, but sometimes can be 

asymptomatic. When it does cause symptoms, they are more severe than the common cold 

with less fever and fewer systemic symptoms compared to influenza. LRTI also can occur, 

especially among the immunocompromised, those with underlying cardiopulmonary disease, 

and the elderly. Frequently, RSV can also manifest as exacerbations of chronic medical 

conditions such as chronic obstructive pulmonary disease (COPD), asthma, and congestive 

heart failure. In some case series of immunocompromised persons, RSV can manifest as 

pneumonia and sinusitis, with mortality rates of 50% or more reported. 

This document has been archived for historical purposes. (7/1/2016)
This table shows frequency of symptoms among adults aged 65 years and older: 

 

The most frequent symptoms reported by persons with RSV infection were new or worsening 

cough (92%), headache (82%), fatigue (80%), and nasal congestion (72%). RSV and influenza 

often are thought of commonly as similar pathogens, but they do have different 

symptomologies. As seen in the above slide, fever is reported more frequently in influenza Ainfected persons at 72% versus 56% in RSV in adults.

In terms of the burden of RSV in older US adults, the importance of RSV infections in adults 

was first recognized as a result of outbreaks in long-term healthcare facilities in the 1970s. One 

population based study estimated that RSV infection causes 177,000 hospitalizations and 

14,000 deaths annually1. Another study found that the average annual RSV hospitalization rate 

was 15 per 10,000 residents2. What was striking was that the investigators also found a similar 

rate of hospitalization for influenza. Another study published in 2014 found that there were 154 

medically attended RSV episodes per 10,000 persons in adults 50 years and older with 

increasing incidence with age. This was a prospective study over 4 respiratory seasons in 

community-dwelling older adults who were seeking care for ARI3. For a higher risk group of 

adults 65 years and older, another study found that RSV caused approximately 18 

hospitalizations per 1000 persons and 5 deaths per 1000 persons with chronic lung disease

using retrospective data from the Tennessee Medicaid database4 [1Falsey 2005; 2Widmer 2012; 

3McClure 2014; 4Griffin 2003]. So, there is a burden of RSV in older US adults.

In terms of the virus itself, RSV is an enveloped ribonucleic acid (RNA) Paramyxoviridae virus 

with 2 major subgroups, A and B, which are based on the surface proteins. The viral genome 

consists of 10 genes that encode 11 proteins, two of which are named F and G. The Fusion (F) 

and attachment (G) surface glycoproteins are the most important in their ability to induce 

neutralizing antibodies. The F protein is highly conserved between the RSV subgroups, making 

it a promising vaccine target. Humans are the only source of transmission, and RSV is spread 

by direct or close contact through large droplets or fomites on objects and surfaces. These can 

last from 30 minutes to 6 hours. The incubation period is 4 to 6 days, with a range of 2 to 8 

days. Viral shedding can occur for 3 to 8 days, but can last up to 4 weeks.

There are several methods for testing for RSV or diagnosing it. Laboratory diagnosis of RSV 

can be done by rapid tests of respiratory specimens (midturbinate, nasal swab, or wash). 

These include antigen assays, which are highly sensitive in young children, with reports of 80% 

This document has been archived for historical purposes. (7/1/2016)
to 95% sensitivity. However, they have much lower sensitivity in adults of about 14% to 39% 

due to low virus shedding. Therefore, this is not the optimal way to diagnose RSV in adults. 

Reverse transcriptase polymerase chain reaction (RT-PCR) assays are now more widely 

available and have a much higher sensitivity in adults, with some reports approaching over 

90%. Viral isolation from respiratory specimens in cell culture can also be performed to 

diagnose RSV; however it can take 1 to 5 days, is more expensive, and is less sensitive than 

current methods of RT-PCR. Sensitivity can also be affected by which laboratory is performing 

that method. Serology is used mainly for seroprevalence studies and not for patient care; 

however, the added benefit of serology is that it can add to case finding in adults as studies that 

use both PCR and serology can detect more RSV than virus isolation or PCR alone.

The goal for RSV vaccine development is to safely induce sufficient immunity to protect against 

serious RSV infections like LRTI and possibly apnea in infants. The induction of sterilizing 

immunity is not required and actually might not be feasible. In the late 1960s, a formalin 

inactivated vaccine underwent clinical trials in children 2 months to 7 years of age. 

Unfortunately, there were some devastating results that impacted the development of RSV 

vaccines for several decades. The trials ended when seronegative vaccine recipients had more 

severe RSV-associated LRTIs than non-recipients when they acquired natural infection during 

the subsequent RSV season. Of vaccine recipients, 80% required hospitalization compared to 

5% of controls who never received vaccine. There were 2 deaths in the vaccine recipient group.

 

Data assessing vaccine recipients with serious outcomes from this trial and rodent models 

found that the vaccine caused a vaccine-enhanced disease syndrome in RSV-naïve infants or 

those who had not yet had primary infection. This was due to two main reasons. First, the 

vaccine did not induce enough neutralizing antibody, and second, it induced a Th2- and CD4-

biased immune response leading to more inflammation, more cytokine release, and more 

obstruction and worse outcomes in infants and children. There are many implications of the 

formalin-inactivated vaccine trial, including the fact that vaccine development / production 

slowed down due to the need to know more about the immunology of RSV disease and immune 

responses. Because of the enhanced disease seen during the vaccine trials, non-replicating 

vaccines are unlikely to be used in RSV-naïve infants. Therefore, different vaccines types are 

now being used for different target populations. These include replicating or vectored vaccines 

for active immunization of RSV-naïve infants and children, subunit vaccines with or without 

adjuvant for maternal immunization to protect the very youngest infants, and subunit vaccines 

with or without adjuvant to protect the elderly and boost their already-existing immunity. 

Recently, there has been quite some movement in RSV vaccine development as shown on the 

graphic earlier by Dr. Karron. There are more than 60 different products in development by 

several manufacturers. There are different types of vaccines ranging from live-attenuated to 

subunit to those with gene-based vectors. The furthest along is the RSV Fusion protein vaccine 

using recombinant nanoparticle technology developed by Novavax, which will be the first 

vaccine that the ACIP will consider. This vaccine recently completed Phase 3 clinical trials.

There are four RSV vaccine priority groups, which are comprised of the populations at risk of 

severe disease: 









Neonates and Young Infants

Older Infants and Children

Pregnant Women 

Older Adults

This document has been archived for historical purposes. (7/1/2016)
Neonates and young infants have the greatest potential benefit due to having the highest 

burden of disease and mortality among all age groups; however, there are a couple of obstacles 

to think about when developing a vaccine for this age group. They have immature immune 

systems and the presence of pre-existing maternal antibody can make active immunization in 

this age group challenging. Therefore, the most promising strategy for the youngest infants is 

maternal vaccination or administration of an extended half-life monoclonal antibody.

 

Older infants and children face similar issues to young infants, but have more mature immune 

systems and lower levels of maternally acquired antibodies. This should lead to better 

responses to vaccines. Currently, development is focusing on live-attenuated virus and 

vectored vaccines with several candidates in Phase 1 clinical trials.

Pregnant women are also a high risk population. The use of a vaccine for pregnant women has 

several objectives including protecting the young infant by inducing high levels of neutralizing 

antibodies that are transferred to the fetus, preventing maternal to infant transmission of 

infection, and protecting the pregnant woman herself from infection. Pregnant women would not 

be at risk for enhanced disease, given that as infants / children they were already naturally 

exposed and infected. RSV F subunit vaccines are in development, and these candidates are 

in Phase 1, 2, and 3 clinical trials.

Lastly, older adults have a substantial disease burden. However, immunosenscence might be a 

challenge to overcome. Several subunit vaccines are currently in development. Vaccine 

candidates are in Phase 1, 2, and 3 trials. The RSV F subunit nanoparticle vaccine will be the 

first RSV vaccine to be considered for FDA licensure and use, and it is the focus of the current 

ACIP RSV WG.

In August 2015, news media reported early indications of vaccine efficacy of the Novavax 

vaccine targeted for older adults. Early indications show it to be efficacious for RSV in older 

adults. More data will be forthcoming as Phase 2 and 3 trial results become available, and 

these will be presented to ACIP.

As ACIP deliberates the use of an RSV vaccine in older adults, several issues will be 

considered including disease burden, appropriate outcome measures, immunogenicity and 

correlates of protection, duration of protection, the cost-effectiveness of the vaccine, 

implementation issues, and education of stakeholders (particularly among family practitioners 

and other providers who would be administering the vaccine, and the public who would be 

receiving the vaccine). The proposed ACIP timeline will include a review of the epidemiology 

and burden of RSV in older adults in 2016; vaccine manufacturer presentations on clinical trial 

results in 2017; discussions regarding correlates of protection, immunogenicity, and costeffectiveness in 2017; and implementation considerations, the GRADE evidence, and a 

potential vote in 2018.

Introduction and Enhanced Surveillance of Tdap Vaccine Safety in Pregnancy in VAERS

Pedro L. Moro, MD, MPH

Safety of Maternal Tetanus, Diphtheria, Acellular Pertussis (Tdap) Immunization

This document has been archived for historical purposes. (7/1/2016)
Immunization Safety Office

Division of Healthcare Quality Promotion

Centers for Disease Control and Prevention

Dr. Moro reminded everyone that there were two recent ACIP recommendations. The first was

in 2011, which indicated that unvaccinated pregnant women should receive a dose of Tdap to

provide infants with maternal transplacental passive antibody protection against pertussis during

the early postnatal months1

. The next recommendation was a year later, in 2012, to administer

Tdap during every pregnancy, irrespective of prior history of receiving Tdap 2. The optimal

timing for administration is between 27 to 36 weeks gestation. At the time of the

recommendations, limited data were available on the safety of Tdap vaccination in pregnancy

[

1CDC. MMWR. October 21, 2011 / 60(41); 1424-1426. Available at 

www.cdc.gov/mmwr/preview/mmwrhtml/mm6041a4.htm; and 2CDC. MMWR. February 22, 

2013 / 62(07);131-135. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm6207a4.htm. 

During the 2012 deliberations, ACIP expressed the need for enhanced monitoring and safety 

studies of Tdap in pregnancy. The CDC Immunization Safety Office (ISO) implemented a 

comprehensive vaccine safety monitoring effort for maternal Tdap safety1. That included 

enhanced surveillance in VAERS, a clinical review of all Tdap pregnancy reports, epidemiologic 

studies in the VSD, and clinical research in the Clinical Immunization Safety Assessment (CISA) 

Project. In 2015, Tdap vaccination coverage during pregnancy among women who had a live 

birth was 42.1% versus 27% in 20142 [1Moro et al. Hum Vaccin Immunother. 2015;11(12):2872-

9; and 2Pregnant Women and Tdap Vaccination, Internet Panel Surveys, United States, April 

2014 and April 2015 (unpublished data)].

In terms of the safety of Tdap in pregnancy in VAERS, surveillance in VAERS from October 

2011 through June 2015 showed no new or unexpected vaccine safety concerns among 

pregnant women who received Tdap or their infants. These findings were presented at the 

February 2014 ACIP meeting and have been published [Moro PL, et al. Vaccine. 2016 Apr 

29;34(20):2349-53].

There were three studies in the VSD on Tdap in pregnancy, which are reflected in the following 

table, along with the safety data:

This document has been archived for historical purposes. (7/1/2016)
Dr. Moro reminded everyone that VAERS is a passive reporting system that is administered by 

the CDC and FDA. The strengths are that it is capable of rapid signal detection, can detect rare 

AEs, generates hypotheses, encourages reports from healthcare providers and accepts reports 

from patients and others, and makes data available to the public. The limitations include 

reporting bias, inconsistent data quality and completeness, inability to assess whether a vaccine 

caused an AE, lack of an unvaccinated comparison group, and no field for pregnancy status, 

making it difficult to search for reports. Because there is no denominator, it is not possible to 

calculate the incidence or prevalence of an AE or to estimate the risk of an AE.

Surveillance was initiated on November 26, 2012. The VAERS database was searched for 

reports of pregnant women after administration of Tdap vaccinated from 10/11/2011 through 

5/6/2016. Medical records were requested and reviewed for all pregnancy reports associated 

with Tdap. The reporter / patient was also queried for prior administration of tetanus-containing 

vaccine. 

VAERS received a total of 464 pregnancy reports after Tdap. In 54% of reports, the 

manufacturer was the reporter. The majority (85%) of Tdap doses were give alone. There were 

26 (5.6%) reports of repeat doses. For a majority of the reports (80%), Tdap was given during 

the third trimester. In terms of pregnancy-specific AEs, the two most commonly reported 

conditions were premature delivery (< 37 weeks) and stillbirth. Regarding fetal or infant AEs, 

one neonatal demise was reported to VAERS. Four major birth defects were reported: ectopic 

kidney in newborn, hypoplastic left heart syndrome, Trisomy 12, and clubbed foot. The 

predominant non-pregnancy specific AEs included injection site reactions and systemic 

reactions. Regarding reports of repeat Tdap doses among pregnant women, 26 were reported 

to have received a previous dose of Tdap. The interval between current and previous Tdap was 

7 days to 9.4 years, with a median of 1.8 years. Thirteen reports did not describe an AE. AEs 

in 13 reports included:

This document has been archived for historical purposes. (7/1/2016)






4 reports of injection site or arm pain

2 reports each of oligohydramnios, intrauterine growth restriction / poor fetal growth, and 

elevated blood pressure / abdominal pain

1 report each of stillbirth with trisomy 12, maternal urinary tract infection, and maternal 

systemic reactions (e.g., fever, chills)

In conclusion, in VAERS no new unexpected vaccine safety concerns were noted among 

pregnant women who received Tdap or their infants. A limited number of pregnancy reports 

with repeat Tdap doses were received by VAERS. CDC will continue to monitor the safety of 

Tdap vaccine during pregnancy. 

Discussion Points

Dr. Hayes (ACNM) asked what the rate of GBS is in the general population who received Tdap 

compared to the maternal vaccination group.

Dr. DeStefano (SME) responded that he did not think they had those specific rates. Pregnancy 

is a risk factor for GBS, but there are no data to suggest that maternal receipt of Tdap 

vaccination is associated with GBS. 

Maternal Pertussis Vaccination and Structural Birth Defects in Offspring

Lakshmi Sukumaran, MD, MPH 

Immunization Safety Office

Centers for Disease Control and Prevention

Dr. Sukumaran indicated that she would be presenting the VSD study on behalf of the Health 

Partners Institute VSD team. Tdap vaccine has been recommended for routine use in pregnant 

women not previously vaccinated since 2010 in California and since 2011 across the US. In the 

fall of 2012, ACIP recommended that Tdap be administered during every pregnancy, with a 

preference for it to be given between 27 through 36 weeks gestation. Many other countries also

have implemented maternal Tdap vaccination programs.

 

The objective of the Health Partners Institute VSD team study was to examine risks for 

structural birth defects following maternal Tdap vaccination within the VSD. The study 

outcomes were any birth defect, major structural defects, and microcephaly. Microcephaly in 

particular was chosen as an outcome because in Brazil, there is a maternal Tdap immunization 

program and there was some speculation initially that increases in microcephaly were due to 

maternal Tdap vaccine and not Zika virus.

The 7 VSD sites that contributed data to the study on Tdap in pregnancy included the following:















Group Health Cooperative

Northwest Kaiser Permanente

Kaiser Permanente Northern CA

Kaiser Permanente Southern CA

Kaiser Permanente Colorado

HealthPartners

Marshfield Clinic

This document has been archived for historical purposes. (7/1/2016)
In a study of coverage data on maternal Tdap vaccination in live births between 2007 and 2013 

within the VSD that was published earlier this year, there was a steady background rate of first 

trimester vaccinations during the study period. This usually represents women who did not 

realize that they were pregnant at the time of vaccination. However, it is an important for this 

study because most birth defects occur in the first trimester. There was a large increase in 

vaccinations in 2010 related to the California vaccine recommendations and in 2013 following 

the ACIP recommendations [Kharbanda et al. Vaccine 2016].

An observational cohort study was conducted of pregnant women and their infants from the 7 

VSD sites. Pregnancies ending in a live birth between January 1, 2007 and September 1, 2013

were studied. Pregnancies were identified through a validated algorithm based on 

administrative electronic health record and birth certificate data [Naleway et al. Vaccine. 2013]. 

Pregnant women were included who had continuous insurance enrollment from 6 months prior 

to their last menstrual period (LMP) through 6 weeks postpartum, with at least 1 outpatient visit 

during pregnancy. Infants were required to have birth weight and gestational age available. If 

they survived to 12 months of age, they were required to have 4 months of insurance 

enrollment, with 1 outpatient visit during the first year of life. For infants who died during the first 

year of life, these insurance and health utilization criteria were not applied. 

Exclusions were identified from International Classification of Diseases (ICD)-9 codes and 

pharmacy files. Multiple gestation births and live births with a known exposure increasing their 

risk for a structural birth defect were excluded, including receipt of a live virus vaccine during 

pregnancy, pre-existing diabetes, use of a teratogenic medication, infant congenital TORCH 

infections (toxoplasmosis, other, rubella, cytomegalovirus, and Herpes simplex), and infant 

chromosomal abnormalities. Maternal Tdap administrations were identified using claims and 

EHR data found in standardized VSD files. Three exposure windows were assessed: 

This document has been archived for historical purposes. (7/1/2016)






First trimester, defined as <14 weeks gestation, which is the most biologically plausible 

time period for a birth defect to occur

27 to 36 weeks gestation, which is consistent with current ACIP recommendations for 

optimal timing of maternal Tdap administration

Any week during pregnancy, since Tdap can be given at any time during pregnancy

Three neonatal outcomes were examined that were identified from inpatient, outpatient, or 

emergency visits during an infant’s first year of life. “Any structural birth defect” was defined by 

the presence of 2 or more ICD-9 codes from 740.0–759.9. For selected major structural 

defects, there was a list of over 50 defects that affect an infant’s life expectancy, health status, 

or physical or social functioning. The major structural birth defects were selected a priori based 

on outcomes monitored in US and European birth defect surveillance systems, and outcomespecific algorithms were developed and applied to increase the specificity for identification of 

major structural defects: For microcephaly, there was also a specific algorithm, which Dr. 

Sukumaran showed an example of as follows:

In general, for major structural birth defects there was a specific code with different outpatient 

and inpatient diagnoses required based on validation work that was done. For microcephaly, 

the code 742.1 would be required with 1 inpatient diagnosis or 2 outpatient diagnoses or 1 

outpatient diagnosis and death in the first year.

For the statistical analysis, baseline characteristics between vaccinated and unvaccinated 

women were compared. Logistic regression was used to estimate aggregate propensity scores 

to adjust for multiple risk factors. The propensity scores included maternal demographic factors, 

healthcare utilization during pregnancy, and maternal comorbidities. Prevalence differences 

were estimated using Poisson distribution with identity link and robust variance. Prevalence 

ratios were estimated using generalized linear models with Poisson distribution.

After applying exclusion criteria, 324,463 pregnancies were included. Of these, 13% were 

Tdap-exposed and 87% were Tdap-unexposed. Over 3,000 women were vaccinated before 14 

weeks gestation and over 20,000 women were vaccinated between 27 and 36 weeks gestation. 

In terms of baseline characteristics of the cohort, maternal age, race, and ethnicity were similar 

This document has been archived for historical purposes. (7/1/2016)
between the groups. Most vaccinated women were 15 through 24 years old. A slightly higher 

percentage of vaccinated women received adequate prenatal care and Tdap vaccinated women 

were more likely to receive another vaccine during pregnancy. Rates of smoking and 

hypertension were similar between the groups.

Regarding the results of the analysis for any structural birth defect following maternal Tdap, 

when Tdap vaccine was given before 14 weeks gestation, the rate of any structural birth defect 

was 6.3% compared to 6.2% in unexposed women. For 27 through 36 weeks gestation, 7% of 

Tdap-exposed and Tdap-unexposed had a structural birth defect. For Tdap at any time during 

pregnancy, 6.8% compared to 6.2% of unexposed had a structural birth defect. These 

differences were not statistically significant.

For major structural birth defects, when Tdap was given before 14 weeks gestation, the rate 

was 1.8% compared to 1.6% in unexposed women. For Tdap between 27 through 36 weeks 

gestation, the rate was 1.7% compared to 1.6% in unexposed women. For Tdap at any time 

during pregnancy, the rate was 1.7% compared to 1.6% in unexposed women. These 

differences are not statistically significant.

For microcephaly, when Tdap was given before 14 weeks gestation, the rate was 12/10,000 in 

Tdap-exposed and 12/10,000 in Tdap-unexposed. For Tdap administered at 27 through 36 

weeks gestation, the rate was 10/10,000 in Tdap-exposed compared to 12/10,000 in Tdapunexposed. For Tdap at any time in pregnancy, the rate was 9/10,000 in Tdap-exposed 

compared to 12/10,000 in Tdap-unexposed. These differences were not statistically significant.

 

There are some limitations to the study. Birth defects were identified through diagnostic codes 

using the outcome-specific algorithms rather than clinical exam or direct review of charts. There 

is a potential for missing diagnoses in children if they had lapses in their insurance coverage. 

Also, the study was limited to live births. Therefore, it was not possible to study stillbirths, 

elective terminations, and spontaneous abortions. 

In summary, maternal Tdap vaccination during pregnancy was not associated with increased 

risk for birth defects, including microcephaly, among live birth offspring. These results support 

the safety of maternal Tdap vaccination for the infant outcomes evaluated. 

 

Discussion Points

Dr. Harrison inquired as to why a record review was not done for at least a subset of the ICD-9 

codes.

Dr. Sukumaran replied that a record review was done when the algorithms were being 

developed for identifying the birth defects to make sure that the codes were valid, and to make 

sure that the background rates in the VSD were similar to national background rates. That

algorithm was then applied to the larger dataset.

Dr. Reingold was curious as to why the investigators did not assess the effect of giving vaccine 

in the interval between 15 through 26 weeks. Given that ACIP is considering the potential for 

recommending the vaccine earlier in pregnancy, it might be of interest to do that calculation and 

show it.

This document has been archived for historical purposes. (7/1/2016)
Dr. Sukumaran responded that this group was included in the “Tdap given at any time during 

pregnancy” group. If the recommendation changes for the timing of administration, this group 

can be assessed more carefully.

Given the furor in the discussion about the 2011-2012 recommendations by many ACIP 

members and liaisons at that time, Dr. Baker (IDSA) congratulated the investigators on 

performing this study. The second trimester will be assessed and evaluated, and that 

information will be needed moving forward. She found these data to be beautiful and very 

reassuring.

Dr. Sukumaran responded that they do have the data on the second trimester, so it is possible 

to evaluate this closely as well.

Reactogenicity and Immunogenicity of Tdap Vaccine in Pregnant Women

Kathryn Edwards, MD

Vanderbilt University School of Medicine

Dr. Edwards provided an overview of the clinical study of Tdap safety during pregnancy, and 

preliminary results from the reactogenicity and immunogenicity analyses. ACIP has 

recommended that providers administer a dose of Tdap during each pregnancy, with the optimal 

timing being 27 to 36 weeks gestation. Available data support the safety of Tdap in pregnant 

women, but data on the safety of repeat Tdap doses are limited. As part of a comprehensive 

monitoring to evaluate the safety of Tdap in pregnant women, a clinical study was implemented 

in the CDC CISA Project. The primary study aim was to compare rates of injection-site and 

systemic reactions after Tdap in pregnant women versus non-pregnant women. The secondary 

study aim was to explore differences in injection-site and systemic reactions in pregnant women 

who received Tdap before the current pregnancy versus pregnant women receiving their first 

Tdap dose. There also were two exploratory aims funded by a Bill and Melinda Gates 

Foundation grant to Vanderbilt, which were to:





Measure antibody levels to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin 

(PRN), fimbria (FIM) and diphtheria and tetanus toxoids prior to and one month after 

administration of Tdap vaccine in both pregnant and non-pregnant women; and 

Compare levels of cytokines in women (pregnant and non-pregnant) with severe local or 

systemic reactions after Tdap with those without reactions, using measurements of 

cytokines before, during, and after the reactions.

There are additional studies in progress to:







Assess the rates of preterm and small for gestational age (SGA) births in women who 

received Tdap during pregnancy; 

Assess the rates of additional obstetrical and infant outcomes in pregnant women receiving 

Tdap (e.g., pregnancy related hypertension); and

Describe the health outcomes and growth parameters through 6 months of life among 

infants born to women who received Tdap during pregnancy. 

This document has been archived for historical purposes. (7/1/2016)
In terms of the methods, this is a prospective observational study of women 18 through 45 years

of age receiving Tdap as first or repeat doses at Vanderbilt and Duke University clinics. 

Pregnant women ≥ 20 and ≤ 34 weeks gestation were enrolled in the study. These women 

received Tdap as part of their routine care. The goal of this part of the study was to enroll 375 

pregnant women. Non-pregnant women receiving Tdap for usual care or as part of a research 

procedure and followed through 1 month after vaccination also were enrolled. The goal was to 

enroll 225 non-pregnant women. Prior Tdap, Td, or TT history was assessed by subject report, 

medical record review, or state registry to document vaccine receipt. Rates of local and 

systemic reactions were assessed during Days 0 through 7 after Tdap using memory aid with 

severity scales. Blood was collected on Days 0 and 28 after Tdap. Pertussis serology studies 

were performed at Vanderbilt, while the diphtheria/tetanus toxoid serologies were performed at 

Duke. Blood was collected in women with severe local and systemic reactions and in controls 

without the reactions for cytokine analysis on Day 0, the day of the reaction, and Day 28. 

Pregnancy outcomes were assessed via chart review, and infant outcomes were assessed by 

phone interview and chart review at 3 and 6 months of life. 

The major statistical analysis was directed at non-inferiority analysis for reactogenicity because 

the study was really looking at the safety of the vaccines. For this purpose, comparisons were 

made of the proportions with moderate to severe and severe reactions during 0 to 7 days postvaccination between pregnant women and non-pregnant women receiving Tdap, and between 

pregnant women who received prior Tdap and those with no prior Tdap receipt. The primary 

hypothesis was that the rates of moderate to severe reactions in pregnant women receiving 

Tdap would be non-inferior to non-pregnant women receiving Tdap. One sided statistical tests

were used, with a non-inferiority margin of 10% for moderate to severe and 5% for severe 

reactions. 

The mean age, gestational age, and gestational weeks at delivery at both study sites were

comparable and the same as seen in other studies presented during the morning. There was 

also prior Tdap receipt in about 50% of the pregnant women at Vanderbilt, about 65% at Duke, 

and indeed a higher percentage had received prior Tdap, Td, or TT. In addition, because of 

vaccine availability at pharmacies, almost all vaccine administered was Sanofi Pasteur’s 

Adacel® vaccine. A small proportion received Boostrix® vaccine. By and large, these women 

had participated in other vaccine studies and received other vaccines prior to the Tdap vaccine. 

For the non-pregnant women at the study sites, the mean age was very similar. Prior Tdap 

receipt was 60% at Vanderbilt and almost 80% at Duke. The non-pregnant women often were

under the care of healthcare providers, which may explain their higher rate of prior Tdap receipt. 

Tdap, Td, and TT receipt was also very high in this group. All of the women in the non-pregnant 

group at Vanderbilt received Adacel® and about two-thirds at Duke did as well. Again, many of

these women had received influenza vaccine the previous year.

Regarding local reactions within the 7 days after vaccination in pregnant versus non-pregnant 

women, the following definitions were used:





Moderate: Induration and erythema: 10-34 mm; Pain/tenderness: Interferes with activity but 

did not necessitate medical visit or absenteeism

Severe: Induration and erythema: >=35 mm; Pain/tenderness: Prevents daily activity and 

resulted in medical visit or absenteeism

This document has been archived for historical purposes. (7/1/2016)
 Non-inferiority criteria met for moderate/severe and severe local reactions in pregnant vs. 

non-pregnant women, except moderate/severe pain

The rates of pain were greater in the pregnant women. The rates of tenderness, swelling, and 

redness did not differ between the pregnant and non-pregnant groups. Very few severe 

reactions were observed in the pregnant or non-pregnant women, and did not differ in their 

rates.

Comparing the proportion difference between pregnant and non-pregnant women, moderate to 

severe pain did reach the 10% or higher level in pregnant women. The biology that would 

explain this is not clear. In terms of systemic symptoms after vaccination, moderate fever was 

defined as ≥ 100.4 to < 102.2° F and other symptoms that interfered with activity but did not 

necessitate medical visit or absenteeism. Severe fever was defined as ≥ 102.2° F and other 

symptoms that prevented daily activity and resulted in medical visit or absenteeism. The rates 

of moderate to severe systemic reactions were comparable in the pregnant and non-pregnant 

groups for fever, feverishness, malaise, body aches, and headaches. 

All comparisons for moderate to severe or severe reactions met non-inferiority criteria

among pregnant women with and without prior Tdap receipt. There were no significant 

differences, and no indication that prior Tdap vaccination would predispose one to more 

reactions. For systemic and local reactions, when women are compared who had Tdap before 

to those who did not, there were no significant differences in any of the reactions at the 10% for 

moderate or severe reactions. It is reassuring that repeated Tdap does not appear to program 

one for more severe local or systemic responses. No women sought medical care for a vaccine 

reaction, and no SAEs were reported. 

In terms of the serologic studies, for each of the pertussis antigens in both the pregnant and 

non-pregnant women, the antibody responses were significantly higher post-vaccination for all 

of the antigens. When the ratio of the pre and post-vaccination antibody titers (non-pregnant: 

pregnant women) was compared for all the pertussis antigens, some differences were shown. 

The ratio was significantly > 1.0 for PT and FHA titers post-vaccination and for FIM and PRN 

pre-vaccination. This means that non-pregnant women had significantly higher antibody titers at 

28 days after vaccinations for PT and FIM and had significantly higher antibody titers at Day 0 

for FIM and PRN when compared to pregnant women. The non-pregnant women had higher 

rates of prior immunizations and may have explained why they had higher pre-vaccination titers 

for FIM and PRN. Why they had higher post-vaccination titers for PT and FIM is not clear. 

Comparing the ratio of those antibody titers to those who had not received Tdap before and 

those who had, for all of the pre-antibody titers, the no Tdap before had a lower ratio, meaning 

that the antibody titers in no Tdap before for pre-titers were all significantly less. Again, this may 

have reflected the higher titers in the women who received Tdap before reflected in their pretiters. What is interesting, however, is that for the FIM and PRN, the antibody titers were higher 

in those who had not had prior Tdap. It is not clear whether that reflects immune suppression or 

is a statistical fluke. But again, all of them had antibody rises.

Regarding the cytokine study, 6 subjects had severe reactions. They were seen at the time of 

the severe reactions. They were matched to 6 controls who did not have severe reactions who 

were seen at that same time, and were matched by pregnancy status. There were 5 cases at 

Vanderbilt, 2 of whom were pregnant and 3 of whom were not. There was 1 non-pregnant case 

at Duke. They were matched for their pregnancy status. For each of the cytokine levels at each 

This document has been archived for historical purposes. (7/1/2016)
of the determinations, there were no significant differences between the cases and the controls. 

Also, there were no differences in the cases before and after vaccination or the time of local or 

systemic reactions for IL-6, IL-8, IL-10, TNF-α, and IL-5.

In conclusion, Tdap was well-tolerated in both pregnant and non-pregnant women. Moderate

and severe injection-site pain occurred more frequently among pregnant women, but rates were 

consistent with clinically reported rates for the Tdap vaccine (16% per Adacel® package insert) 

and did not lead to medical visits. Of the pregnant women, 53% received a prior Tdap vaccine 

and rates of moderate and severe reactions were similar in pregnant women receiving the first 

or repeat Tdap vaccine. Both pregnant and non-pregnant women had significantly higher 

antibody titers to all antigens after vaccination. Obstetric and fetal outcome data are being 

collected. 

Discussion Points

Dr. Karron wondered whether the antibody responses had been analyzed by gestational age.

Dr. Edwards responded that they did assess this. Unfortunately, they were so adherent to the 

study criteria, there was little variability in when women received the vaccine. Therefore, this 

cannot be addressed adequately.

Dr. Reingold asked whether there were any women in the study for whom it was a third 

pregnancy and who were receiving a third dose of Tdap.

Dr. Edwards replied that they did not have these data.

Dr. Baker (IDSA) asked whether Dr. Edwards could comment on the possibility of differences in 

circulating pertussis in the community among the two groups, and whether the study was 

performed at a time when pertussis activity was high, medium, or low.

Dr. Edwards responded that at the time of the study, the investigators did not appreciate that the 

issues regarding circulation of pertussis were occurring at either site. They did not have 

ongoing serologic studies that might have evaluated that. They have not assessed duration of 

antibody in this particular study, although they are in the process of analyzing data funded by 

NIH in which antibody titers were assessed over two years in women who were vaccinated postpartum. The antibody titers drop off very fast, which is very curious because for tetanus and 

diphtheria they do not. This is very interesting. Even in those patients, at two years there were 

still some antibody titers for some of the antigens. Some of these women were vaccinated 

within a year or so in the non-pregnant group. It is hard to say, but the investigators do not 

believe that there was natural transmission. Pertussis is a complicated problem.

Ms. Stinchfield (NAPNAP) noted that Dr. Edwards had used the words “reaction” and 

“response.” When vaccinating pregnant women and they get local redness and swelling, a 

pregnant woman might hear “a vaccine reaction equals I can’t have another one in the future.” 

To turn that to a positive, that is a robust immune response.

Dr. Edwards said that for many years, an attempt has been made to determine whether having 

a more vigorous local immune response translates to a better serologic response. That is not 

always consistently seen with all antigens. It would be difficult to say whether having a better 

response means having higher antibody. The most reassuring thing she could say about this 

This document has been archived for historical purposes. (7/1/2016)
would pertain to cytokine data. Only 6 people had severe reactions, which is very reassuring. 

Even at the time of the peak local reactions, there were not systemic cytokine responses that 

were elevated. This is very reassuring. It is not clear exactly what will happen in terms of 

repeated Tdap. They did conduct a study a number of years ago that also was funded by the 

CISA Project in which children were assessed at 4 to 6 years who had large local reactions after 

their fourth dose of DTaP at 18 to 24 months, and in general those children did have slightly 

more local responses after their fifth dose than they did at the fourth. However, it was not 

remarkable and there were no severe reactions and no inhibition of activities.

Dr. Sun (FDA) wondered whether anything was found in the assessments of infants at 3 and 6 

months by telephone and chart review.

Dr. Edwards indicated that those are still in the process of being analyzed. All of the patients 

have not reached that mark, but these data should be available soon. Empirically speaking, 

there were no AEs of note.

Pertussis Vaccines WG Update

Art Reingold, MD

Chair, ACIP Pertussis Vaccine Work Group

Dr. Reingold reminded everyone that the Pertussis Vaccine WG was originally formed in April 

2009. Since then, there have been some changes to the composition of the WG. As of June 

2015, the WG had completed all but one remaining term of reference: 

 

Review existing statements on infants and young children (1997), adolescents (2006), 

adults (2006), and pregnant and postpartum women and their infants (2008) and 

consolidate into a single statement.

This consolidated statement was drafted, has been reviewed by WG members, and is making 

its way through CDC clearance.

 

Since 2013, the ACIP recommendation for pregnant women has been as follows:

Health-care personnel should administer a dose of Tdap during each pregnancy, 

irrespective of the patient’s prior history of receiving Tdap. 

The guidance for use states the following:

To maximize the maternal antibody response and passive antibody transfer to the infant, 

optimal timing for Tdap administration is between 27 and 36 weeks gestation.

Since then, several studies from other countries have looked at the immunogenicity of 

vaccinating pregnant women primarily from 27 through 36 weeks gestation. But one study 

prompted the request by CDC to reconvene the WG.

 

Three recently published studies with relevant data show equal or higher antibody 

concentrations among infants whose mothers were vaccinated in the second trimester 

compared to those whose mothers were vaccinated in third trimester1; higher PT antibody levels 

in mothers vaccinated at 28 through 32 weeks compared to those vaccinated 33 through 36 

This document has been archived for historical purposes. (7/1/2016)
weeks2; and no differences in titers of neonatal antibodies between mothers vaccinated in the 

late second trimester and during the third trimester3 [1Eberhardt CS, et. al. Clin Infect Dis. 2016 

Jan 20.; 2Naidu MA, et al. Am J Obstet Gynecol. 2016 Mar 9. [Epub ahead of print]; and

3Vilajeliu A, et. al. Vaccine. 2015 Feb 18;33(8):1056-62]. 

The UK Joint Committee on Vaccination and Immunization changed its recommendation in 

February 2016 such that they now recommend that women receive the vaccine as early as 16 

weeks of gestation, but after the mid-pregnancy ultrasound. Presumably then if there are any 

abnormalities, they cannot be blamed on a dose of Tdap that has recently been given.

The next steps for the WG are to review new data related to Tdap in pregnancy regarding timing 

of vaccination during pregnancy, Tdap effectiveness of preventing pertussis in infants, safety, 

and programmatic considerations. The plan for the October 2016 ACIP meeting is to present 

the consolidated ACIP statement and have additional discussion regarding the timing of 

maternal Tdap vaccination, summarizing the existing data and receiving suggestions from ACIP 

about keeping the timing the same or changing it in the US.

Olen Kew, PhD

National Poliovirus Containment Coordinator (NPCC)

Dr. Kew presented a status report on Poliovirus Type 2 containment in the US. The last wild 

poliovirus (WPV2) in the US was eradicated before 1965, WPV3 around 1968, and WPV1 

around 1970. Globally, WPV2 was last detected in October 1999. Although vaccine strains of 

Type 2 have been detected through the present, indigenous WPV has not been detected since 

that time. Globally, it appears that WPV3 also has been eradicated though WHO is not 

prepared to declare that yet. The last case was in 2012 in Nigeria. WPV1 is barely hanging on. 

Thus far in 2016, there have been about as many cases as occurred in 30 minutes when this 

program began. As of 14 September 2016, there have been 25 cases in only three endemic 

countries: Pakistan has reported 14 cases, with the most recent being 27 July; Afghanistan has 

reported 8 cases, with the most recent occurring 8 August; and Nigeria has reported 3 cases, 

with the most recent detected in 6 August.

The goal of the WHO Global Action Plan on Poliovirus Containment, Third Edition (GAPIII) is to 

minimize poliovirus facility-associated risk after type-specific eradication of WPVs and 

sequential, type-specific cessation of oral poliovirus vaccine (OPV) use. The original hope was 

to eradicate all three serotypes in such a close time span that there could be a coordinated, 

concurrent containment of all three poliovirus serotypes. However, because of the long lag after 

the eradication of Type 2 and the occurrence of repeated outbreaks associated with Type 2 

circulating vaccine-derived polioviruses, it became clear that Type 2 had to be contained 

specifically. Therefore, implementation is in three phases. Phase I was Global Coordination 

and Readiness, Phase II is Poliovirus Type 2 Containment by 2016, and Phase III is Complete

Poliovirus Containment (all three serotypes) at least three years after the last WPV 

case/infection. The date for completion of Phase III depends on the timeline of WPV eradication 

in the remaining endemic countries. All “infectious” and “potentially infectious” poliovirus 

materials were requested to be inventoried by the end of 2015, although this was not 

accomplished. Not only WPV and OPV/Sabin of all three serotypes, but also vaccine-derived 

Laboratory Containment of Poliovirus Type 2

This document has been archived for historical purposes. (7/1/2016)
polioviruses (which are phenotypically indistinguishable from WPVs). Some vaccine-derived 

polioviruses have circulated in communities for as long as 10 years. The objective is to reduce 

the number of facilities handling poliovirus to a minimum. The following graphic depicts the 

phases of GAPIII. 

One of the key events was the withdrawal of OPV Type 2 from the vaccine by May 2016. The 

last dose of trivalent OPV was given before mid-May 2016, and a shift was made to a bivalent 

Type 1 and 3 vaccine. That poses a biological imperative to containing Type 2 in the US, and 

particularly in developing countries. The long-term plan is to cease the use of bivalent OPV as 

well and shift to IPV. Within that, WPV and vaccine-derived Type 2 poliovirus must be 

contained in what are known as “Poliovirus Essential Facilities” in 2016. An approach is being 

used that will phase in the strategy. “Containment” means to act on three options: 1)destroy 

and document destruction of all unneeded poliovirus infectious or potentially infectious 

materials, 2) transfer important materials to a Poliovirus Essential Facility, or 3) become a 

Poliovirus Essential Facility by implementing facility and personnel performance standards 

required by GAPIII.

In terms of the US role in global containment, Dr. Walter Dowdle initiated a survey in 2002–2003 

that showed that 34% of all facilities worldwide storing WPV infectious or potentially infectious 

materials were in the US. CDC has the largest WHO Global Polio Reference Laboratory. The 

US is home to many leading poliovirus research institutions. There is no polio vaccine 

production in the US, but there is ongoing vaccine testing. While the risks of facility-associated 

poliovirus infections in the community in the US are low, they are not zero. The risks are much 

higher in developing country settings. The US has a responsibility to take a leading role and set 

a good example. The US National Poliovirus Containment Coordinator (NPCC) reports to the 

US National Certification Committee (NCC), the NCC reports to a Regional Certification 

Commission (RCC), and the RCC reports to the Global Certification Commission (GCC). The 

GCC ultimately will declare the eradication of polio worldwide, as was done previously with 

smallpox.

This document has been archived for historical purposes. (7/1/2016)
The NCC Task Force for Global Health in Decatur, Georgia is the Secretariat for the NCC, 

which is constituted by the eminent experts in their fields:















Chair: Kenneth I. Berns, MD, PhD, Distinguished Professor Emeritus, Molecular 

Genetics and Microbiology, University of Florida 

Charles Brokopp, DrPH, Laboratory Director, Wisconsin State Laboratory of Hygiene

Megan Davies, MD, Acting State Health Director, State Epidemiologist and Chief, North 

Carolina Division of Public Health

Joseph Kanabrocki, PhD, CBSP, Associate Vice President for Research Safety, 

University of Chicago

Ruth Lynfield, MD, State Epidemiologist and Medical Director, Minnesota Department of 

Health

José Romero, MD, FAAP, Chief, Pediatric Infectious Diseases; Director, Clinical Trials 

Research, Arkansas Children's Hospital Research Institute

Dominica (Dee) Zimmerman, University of Texas Medical Branch, Environmental Health 

and Safety

The 2002–2003 survey was implemented among 105,356 individual laboratories in 32,429 

institutions. Only 180 laboratories reported storage of WPV infectious or potentially infectious 

materials. The survey did not ask about serotype. This included 12 CDC laboratories. The 

2002–2003 polio survey came in wake of the Select Agent Act and had a very high response 

rate, which may not have been coincidental. The survey queried only about WPV materials, not 

OPV/Sabin strains. There was no differentiation by serotype. The findings from the 2002–2003 

survey were the starting point for a 2015–2016 survey conducted by the Office of the NPCC 

based at CDC, which reports to CDC, NCIRD, NCC, and the Office of Assistant Secretary of 

Health (OASH) through National Vaccine Program Office (NVPO), directed by Dr. Bruce Gellin. 

CDC developed a web-based survey instrument that was modified from the original 

WHO/PAHO (Pan American Health Organization) template. The initial contact is by email. Two 

surveys were distributed, one of which was an internal CDC survey that was launched 14 

December 2015 in an effort to comply with the 12 November request from the Director General 

of WHO to have this job completed by the end of 2015. The second was an external survey that 

was launched serially with the first launch 22 December 2015 among federal facilities, academic 

institutions, state and local health departments, industrial facilities, commercial diagnostic 

laboratories, and hospitals. The initial response rate was not very high, but has now risen to 

82%.

NPCC’s approach to containment was distribution of the survey by prioritization of the estimated 

risk. Phase IIa was containment of WPV2 and VDPV2 infectious materials. The top priority was 

academic laboratories that had been working with WPV2 and VDPV2 recently. The second 

priority was containment of potentially infectious materials. Phase IIb included the third priority 

of containment of OPV2/Sabin 2 infectious materials, and the fourth priority is OPV/Sabin 

potentially infectious materials. The priority categories frequently overlap, which was clear from 

the responses received. This was an opportunity to contain all PV and be removed from the list 

for the facility. Potentially infectious materials have been prioritized by risk, assigning the 

highest risk to stool specimens.

Surveys have been launched in successive waves, prioritizing by estimated risks. The highest 

priority has been assigned to WPV2 strains and enteric specimens, while the lowest priority has 

been assigned to domestic respiratory specimens and nucleic acids. Containment is an 

ongoing process. The immediate goal is PV2 containment in 2016. The overall goal is full 

This document has been archived for historical purposes. (7/1/2016)
poliovirus containment, potentially as early as 2019. The survey results are used to guide the 

priorities for subsequent survey rounds. A collaborative approach to laboratories has been 

taken. The NPCC office has been assisted greatly by Biosafety Officers for coordination and 

further follow-up. NVPO assistance will be sought for chronic non-responders.

In terms of the internal CDC survey, CDC is the largest facility storing poliovirus infectious and 

potentially infectious materials. Containment receives strong institutional support. The CDC 

Polio Laboratory is the major WHO Global Polio Reference Laboratory, and contains the largest 

poliovirus collection in the world. It is the only CDC laboratory with WPV2/VDPV2 infectious 

materials. All WPV2/VDPV2 were moved to a containment laboratory and 189,763 vials of 

poliovirus infectious or potentially infectious materials in the CDC Polio Laboratory were 

autoclaved by 24 May 2016. Other CDC laboratories store poliovirus potentially infectious 

materials comprised of historical US and international specimens. All 149 CDC laboratories 

were contacted and completed the survey by 15 March 2016.

The external survey was launched in successive waves, with the first launch in December 2015. 

The survey was distributed to 113 laboratories identified in a 2002–2003 survey as storing WPV 

materials (other facilities identified in 2002–2003 were no longer operating). Special attention 

was given to laboratories known to be performing current research / testing with WPV2. There 

was a re-launch to first-round non-responders as well as subsequent launches to newly 

identified laboratories, state and large municipal health laboratories, other non-polio enteric 

virology laboratories (rotavirus, norovirus, astrovirus, Hepatitis A virus, Hepatitis E virus, et 

cetera) and enteric bacteriology laboratories. There is less concern about enteric bacteriology 

and parasitology laboratories, given that they do not normally store original stool specimens 

after isolation of infectious agents. However, enteric microbiome/metagenomics laboratories do 

retain specimens for reinvestigation as methods improve. There has been a significant amount 

of assistance from Biosafety Officers of large institutions to help fill any remaining gaps. There 

were 178 responses to the internal survey as of September 6, 2016. The major academic 

laboratories responded early. Most of the laboratories that responded later have worked with 

reference strains or have stored reference strains primarily for serology. More laboratories work 

with Type 1. Type 2 is not the favorite one for most research laboratories. The same is true 

with the Sabin strains.

There are a number of challenges. Some interpretations at WHO headquarters of GAPIII 

requirements are very prescriptive, and they are becoming an impediment to compliance. Highrisk infectious materials and low-risk potentially infectious materials such as respiratory 

specimens and nucleic acids are grouped together for containment in GAPIII, without any real 

appreciation of the great differences in potential risk. WHO is aware of these challenges and 

has empaneled a Containment Advisory Group to help guide the way forward. Absence of 

statutory authority could limit compliance outside of federal government facilities. While this has 

the potential to limit compliance, that has not been the experience. The process for issuing 

certificates to Poliovirus Essential Facilities is incompletely defined. Potentially infectious 

materials, especially of OPV/Sabin variety, present challenges for outreach. Respiratory virology 

/ microbiology laboratories have particular concerns about how poliovirus containment might 

adversely impact their vital work. Academic laboratories, with frequent student turnover, 

present special challenges to specimen management and containment. Non-poliovirus and 

non-virus laboratories are not generally aware of poliovirus containment. Some may store 

potentially infectious materials. Absolute poliovirus containment is not feasible. Undetected 

vaccine-derived excretion is likely to continue. For example, a patient in the UK has been 

excreting for nearly 30 years, and one chronically-infected patient went undetected for 13 years 

This document has been archived for historical purposes. (7/1/2016)
in the US. That is likely to continue. Poliovirus can be easily prepared by synthetic biology, 

fortunately and unfortunately. GenBank® sequence data exists in perpetuity. The goal must be 

major reduction of risk, which is feasible provided that colleagues are constructively engaged.

In terms of an example of the impact of Type 2 containment on US vaccination policy, the 

general recommendations for children with low or questionable documentation of vaccination 

are to take an alternative approach rather than just giving IPV, which would be the preferred 

approach. That would be serologic testing for neutralizing antibody to all three serotypes. This 

can be obtained commercially and at certain state health department laboratories, although 

there is limited availability. Persons with protective titers against all three types do not need to 

repeat doses, but should complete the schedule as age-appropriate. The alternative approach 

may no longer be feasible because commercial facilities are no longer working with Type 2, so 

they suspended Type 2 antibody in response to the request for them to contain their Type 2 

strains [This information courtesy Mona Marin and Manisha Patel DVD/NCIRD/CDC].

Discussion Points

Dr. Ezeanolue asked whether consideration had been given to anticipated uptake in terms of 

moving from OPV to IPV, especially in countries like Nigeria.

Dr. Kew responded that this has been part of the plan for some time. There has been difficulty 

in Nigeria even administering OPV. While he did not know the acceptance rate precisely, 

enormous effort has been invested in each country to raise coverage rates to as high as 

possible. The weaknesses in the overall strategy is that routine immunization is low in some 

countries, especially in Nigeria where coverage is strong in the South and much weaker in the 

North. Successful IPV door-to-door campaigns have been conducted in Kenya. It remains 

unclear how high coverage rates will be with the shift away from trivalent OPV. However, the 

bivalent OPV will continue to be used. The bivalent will not be suspended until all three 

serotypes are eradicated. The problem with Type 2 in recent years has been the Type 2 

vaccine-derived polioviruses from the trivalent vaccine. Once that is removed, it is not 

anticipated that this will be as serious a problem. Routine immunization rates must be raised as 

much as possible worldwide.

Dr. Romero emphasized that this has been a Herculean effort that has been shepherded and 

led by Dr. Kew, who deserves a lot of credit for assembling these data.

Given that it is stored in laboratories throughout the US, Dr. Smith wondered how the infectious 

material is destroyed, where this is done, and whether it has to be shipped.

Dr. Kew responded that the virologists and microbiologists are well-trained in how to destroy 

poliovirus. They simply put it in the autoclave and it is destroyed. All of the laboratories have 

autoclaves, which allows them to destroy the virus readily. There are a number of other ways 

as well. The greater challenge has been to destroy the trivalent OPV stocks so that they are 

never used again in the field.

Dr. Cohn requested that someone discuss the plan to address the serology alternative 

approach.

This document has been archived for historical purposes. (7/1/2016)
Mona Marin indicated that an effort is being made to assess the scope of this problem. There 

has been informal contact with companies that have been providing this service. There are 

certain state laboratories that also have been providing it. The second part is understanding the 

degree to which that particular element in Table 14 in the General Recommendations has been 

incorporated into either local regulations or even in the case of some federal facilities. 

Currently, they are at the data gathering stage trying to understand the scope of this problem in 

terms of providing that service and the impact to state, local, and federal institutions due to 

using this particular element of the General Recommendations. At that point, it is anticipated 

that the change would be proposed to remove it.

Dr. Koger indicated that post-ACIP vote on CDC clearance in September 2015, the language 

was taken out to offer serology as an alternative approach. Revaccination is now the primary 

approach per the CDC-level cleared draft of the General Recommendations for people 

vaccinated outside of the US who enter the US with questionable records. This is going through 

clearance currently, so at least from an implementation perspective, that language should be 

published soon.

Dr. Sun (FDA) asked whether the long-range plan was to continue with polio vaccination until 

eradication, or if there is an anticipation that vaccination of laboratory workers would be 

continued just in case they are exposed.

Dr. Kew replied that the long-term plan would be to use IPV for an indeterminate period of time, 

and assess the risks moving forward. There is no date set for the cessation of IPV use. It may 

simply become part of a multi-antigen vaccine that is used for many years. Some countries 

have stated that they will be using IPV indefinitely, depending upon its availability and a number 

of other factors. Continued use will depend upon the epidemiology moving forward.

Introduction

Allison Kempe, MD, MPH

Chair, ACIP HPV Vaccines WG 

Dr. Kempe reminded everyone that the WG has been reviewing evidence on HPV vaccine 2-

dose schedules. During the February 2016 ACIP meeting, the HPV session focused on data 

from the 2-dose immunobridging trial. The June 2016 session provided further evidence 

needed for consideration of a 2-dose HPV vaccination schedule that the WG hoped would result 

in a vote during the October ACIP meeting.

During the February 2016 meeting, background information was provided on 2-dose schedules; 

data were presented from the 9-valent HPV vaccine 2- versus 3-dose immunogenicity trial, 

which showed non-inferior immunogenicity with 2 doses using either a 0, 6 month or 0, 12 

month schedule in 9 through 14 year olds compared with 3 doses using a 0,2,6 month schedule

in 15 through 26 year olds. Subsequently, a sBLA was submitted to the FDA in early 2016. 

Bivalent and quadrivalent HPV vaccine 2- versus 3-dose immunogenicity data and HPV WG 

plans also were presented at the ACIP meeting in February 2016.

Human Papillomavirus (HPV) Vaccines

This document has been archived for historical purposes. (7/1/2016)
Since February 2016, the WG has reviewed data on duration of protection after HPV 

vaccination and on post-licensure effectiveness studies, drafted policy questions, conducted a 

systematic literature review and completed initial GRADE evaluation of evidence for 2-dose 

schedules, and discussed considerations for recommendations. 

During this session, presentations were given on the following topics:











Duration of protection after HPV vaccination

Modeling and cost-effectiveness of 2-dose schedules

Review of vaccine effectiveness studies

GRADE for 2-dose schedules

Initial considerations for recommendations

HPV Vaccine Availability in the US / HPV Vaccine Duration of Protection

Lauri Markowitz, MD

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Markowitz began by mentioning the status of HPV vaccine availability in the US since this 

would impact some of ACIP’s discussions and approaches. There are 3 HPV vaccines licensed

in the US: Quadrivalent (4vHPV), bivalent (2vHPV), and 9-valent (9vHPV). Through 2014, 

almost all HPV vaccine used in the US was 4vHPV. 9vHPV was licensed in 2014 and was 

recommended in 2015. Currently, almost all vaccine being ordered in the US is 9vhpv. As 

expected with the transition from 4vHPV to 9vHPV, Merck has decided to withdraw 4vHPV from 

the US market by the end of 2016. 4vHPV has not been on CDC vaccine contracts since April 

2016. Regarding 2vHPV, GSK has made a strategic business decision to stop supplying 

2vHPV in the US due to very low market demand. Vaccine supplies in the US are expected to 

be used up by November 2016. 2vHPV has not been on CDC vaccine contracts since April 

2016. GSK will maintain the 2vHPV license in the US. 4vHPV and 2vHPV will continue to be 

available outside of the US. While by the end of the year all vaccine being used in the US will 

be 9vHPV, during this session the WG presented data on 4vHPV and 2vHPV for two reasons: 

1) data from these studies provide information that can inform the discussion about 2-dose 

schedules; and 2) millions of persons have been vaccinated with 4vHPV in the US. 

Dr. Markowitz reviewed data on duration of protection. HPV vaccination is targeted to young 

adolescents to achieve protection of the largest percentage of vaccinees before exposure to the 

virus, but protection is needed through many years of sexual activity. Therefore, long duration 

of protection from HPV vaccination is important and duration could impact the effectiveness of 

vaccination programs. It is important to review available data on duration of protection for a 3-

dose vaccination schedule as ACIP considers reducing the number of recommended doses. 

Another reason the WG presented these data at this time was because the modeling of 2 

versus 3 doses examines different assumptions of duration of protection; understanding 

available t data on duration is needed to put the modeling into context.

In this talk, Dr. Markowitz provided an update on what is known about duration of protection 

from 3-dose HPV vaccines trials as well as immunogenicity data, including persistence of 

antibody and challenge studies to evaluate immune memory by anamnestic response to an 

additional vaccine dose. She also reviewed some data on persistence of antibody from 2-dose 

trials that were presented in February 2016.

This document has been archived for historical purposes. (7/1/2016)
Briefly as background, all available HPV vaccines are virus-like particle vaccines made from the 

L1 major capsid protein of the virus. Vaccines differ in their production system and adjuvants. 

For the bivalent vaccine, the adjuvant is AS04, which includes MPL (3-O-desacyl-4'-

monophosphoryl lipid A) which stimulates Toll-like receptor 4 and enhances the vaccine induced 

immune response. The adjuvant for quadrivalent and 9-valent vaccines is amorphous 

aluminum hydroxyphosphate sulfate. 

 

Data available on duration of protection that Dr. Markowitz reviewed during this session were

from follow-up of randomized clinical trials. Most efficacy and immunogenicity trials had about 3

to 4 years of follow-up. At the end of most of these trials, the control group was vaccinated. 

Extended follow-up for persistence of antibody and infection / disease outcomes was conducted 

for some trials after the original or base trial period was completed. 

The following table lists trials that have data on long-term duration of protection after a 3-dose 

schedule. Included on this table are trials of monovalent HPV 16 vaccine, 2vHPV, and 4HPV: 

Base Trial

Long term 

follow-up 

available (planned) 

Trial Participants

age (yrs)

Trial 

duration 

(yrs)

Reference 

HPV16 phase II efficacy Females 16–23 4 Koutsky, NEJM 2002

Mao, OBGYN 2007

 

8.5

2vHPV Phase II efficacy Females 15–25 2.3 Harper, Lancet 2004 

8.9

4vHPV immunogenicity Females/males 9–15 3 Reisinger, PIDJ 2007 10 

4vHPV phase III efficacy Females 15–26 4 Future II, NEJM 2007 10 (14)

4vHPV phase III efficacy Males 16–26 3 Giuliano, NEJM 2011

Palefsky, NEJM 2011

 8.5 (10)

4vHPV phase III efficacy Females 24–45 4 Castellsague, 

Br J CA 2011

 7.2 (10) 

For the base or original trial shown on the left is the type of trial, population, age group at time of 

vaccination, and the duration of the study in years. The last column, on far right, shows the 

long-term follow-up period with the years of follow-up available and for those not completed,

with the longest planned follow-up time in parentheses.

The monovalent HPV 16 vaccine trial was a proof-of-concept Phase II trial in women aged 16

through 23 years conducted by Merck. At final follow-up, the mean time since first dose was 8.5 

years. Enrollment for the original or base RCT was conducted in 1998-1999 and included over 

2000 women. Vaccine efficacy against HPV 16 persistent infection was 94%, and was 100% for 

cervical intraepithelial neoplasia (CIN). The final follow-up included 290 participants from 

Seattle. During the follow-up period, vaccine efficacy for HPV16 infection was 100%. There 

were no cases of HPV 16-related infection in the vaccine group and 6 in the control group. 

There were no cases of HPV 16-related CIN in the vaccine group and 3 in the control group. 

This document has been archived for historical purposes. (7/1/2016)
The 2vHPV Phase II trial among women aged 16 through 23 years had long-term follow-up with 

a mean of 8.9 years. The base trial was initiated in 2001 and included over 1000 participants. 

Vaccine efficacy for HPV 16/18 persistent infection was 100%. Several follow-up evaluations 

were conducted. The final follow-up included participants from Brazil. This study found vaccine 

efficacy for HPV 16/18 infection was 100% during the follow-up period. There were no 

HPV16/18 infections in the vaccine group and 9 in the control group. There were no cases of 

HPV 16/18-related CIN in the vaccine group and 1 case in the control group. Several different 

follow-up periods were investigated for this study. VE was 95.6% [Naud, Human Vaccin 

Immunol 2014].

The four 4vHPV trials had no unvaccinated control group during follow-up; therefore, there will 

be no efficacy determination in the follow-up studies. The results are disease detection and 

incidence. The 4vHPV immunogenicity trial in adolescents 9 through 14 years of age has 

completed the planned 10 year follow-up. The base RCT included sexually naïve boy and girls. 

Follow-up for effectiveness began after age 16 and there was twice yearly evaluation. The 

population and the median follow-up time for the early and the catch-up vaccination groups 9.9 

years and 7.4 years, respectively. The final 10 year follow-up data from this study were 

presented in June at an international meeting. There were no cases of HPV 6,11,16,18 disease 

in the per protocol population during the follow-up period. Ten persistent infections of >6 

months duration, including 2 of >12 months duration, were detected. All participants with 

persistent infection had antibody to the respective type, and there was no correlation between 

the persistent infection and waning titers for that HPV type. Incidence of persistent vaccine type 

infection per 100 person years ranged from 0.3 to 0.6. For comparison, the incidence of 

persistent 6/11/16/18 infection in the placebo group of trials in 16 through 26 year olds was 

more than 10-fold higher, with males 6/100 person-years and females 4/100 person-years.

For the large 4vHPV efficacy trial in women 16 through 23 years of age, interim 10-year followup data are available. This study will be completed after 14 years of follow-up. The base RCT 

included 12,000 women from 13 international sites. Follow-up is being conducted through the 

Nordic Cancer Registries, which includes women enrolled from Demark, Iceland, Norway, and 

Sweden. Registry searches are done every 2 years. Disease detection was very low. There 

was one case of CIN1 at 6 to 8 years after vaccination. HPV types 16, 45, and 52 were 

detected in the lesion concurrently.

The 4vHPV efficacy trial in males age 16 through 26 years now has 8 years of follow-up. The 

base RCT included over 4000 men from 18 countries. Annual visits are being conducted 

among men enrolled in long-term follow-up, including anal cytology for men in the MSM substudy. There have been no cases of HPV 6,11,16,18 genital warts or external genital lesions in 

the per protocol population in the early vaccine group. There was one case of anal 

intraepithelial neoplasia (AIN)1, with HPV 6 and 58 detected in the lesion concurrently. Again, 

there is no unvaccinated control group, but the risk of AIN was 0.3/100 person years at risk. As 

an historical comparison, the risk of AIN was 5.8/100 person-years in the placebo group of the 

base study. 

In a follow-up of the 4vHPV efficacy trial in women 24 through 45 years of age, interim data 

through 7.2 years of follow-up are available. This was an RCT that included women from 7 

countries. Follow-up is being conducted among women enrolled from Columbia with evaluation

every 2 years. There were no cases of HPV 6,11,16,18 external genital lesions or CIN2+ in the 

per protocol population during the follow-up to date.

This document has been archived for historical purposes. (7/1/2016)
In addition to the studies just reviewed, there are other trials with long-term follow-up planned or 

ongoing but that do not yet have data. These include two 2vHPV Phase III efficacy trials 

(PATRICIA and the Costa Rica Vaccine trial), with planned follow-up of 14 and 10 years, 

respectively, the 9vHPV Phase III efficacy study with planned follow-up of 14 years, and the 

9vHPV immunogenicity study in adolescents with planned follow-up of 10 years. 

Dr. Markowitz briefly reviewed what is known about the immunogenicity of HPV vaccines. There 

is high seroconversion after vaccination: >97% in the clinical trials at one month after the third 

dose. Vaccination induces higher antibody titers than natural infection. Titers peak at 1 month 

after the last dose, decline, and then plateau by 18 to 24 months. The main basis of protection 

is neutralizing antibody. However, the minimum protective antibody threshold is not known. 

The predominant response to vaccination is neutralizing immunoglobulin G (IgG) antibody. It 

also is important to know that the clinical trials of the 2vHPV and 4vHPV vaccines used different 

serologic assays and results are difficult to compare across studies or HPV types. The 2vHPV

trials used an enzyme-linked immunosorbent assay (ELISA), which measured both neutralizing 

and non-neutralizing antibody but detects antibody to one immunoglobulin class. The trials for 

the 4vHPV and 9vHPV vaccine used a competitive Luminex® immunoassay (cLIA), which 

measures antibody restricted to one neutralizing epitope. In clinical trials, some 4vHPV 

vaccinees lost detectable HPV 18 antibody by the cLIA, but there was no loss of protection. In a 

direct head-to-head comparison of the two vaccines using the same assay, antibody titers were 

higher after 2vHPV than 4vHPV vaccination. 

Many of the trials have or are following participants for persistence of antibody in addition to 

infection or disease outcomes. Shown here are the monovalent and 4vHPVtrials with long-term 

available or planned follow-up for persistence of antibody: 

Base Trial Follow-up

Trial Participants (yrs)

Yrs available 

(planned) Seropositive for 

6,11,16,18 Reference 

HPV 16 phase II 

efficacy 

Females 16–23 8.5 86% seropositive for 

HPV 16 in vaccine 

group; 9% in placebo 

Rowhani-Rahbar, Vaccine 2009

4vHPV 

immunogenicity 

Females/Males 9–15

 

10 89%, 89%, 96%, 61% Das and Saah

EUROGIN 2016 

4vHPV phase III 

efficacy 

 

Females 16–23 9 (14) 94%, 96%, 99%, 60% Nygard, Clin Vaccin Immunol 

2015 

4vHPV phase III 

efficacy 

Males 16–26 6 (10) 84%, 87%, 97%, 48% Das and Saah

EUROGIN 2016 

4vHPV phase III 

efficacy 

Females 24-45 8 (10) 89%, 89%, 96%, 61% Das

EUROGIN 2015 

On the left is the base trial with the participant age group, and on the right is the follow-up 

available with the planned number of years in parentheses. These trials have planned follow-up

up to 10 or 14 years. Also included is a summary of the results at the latest follow-up time point. 

The monovalent vaccine trial followed women for 8.5 years. At that time, 86% were positive to 

HPV 16 in the vaccine group compared to 9% in the placebo group. For the 4vHPV 

immunogenicity trial in adolescents, the 10 year follow-up is complete as mentioned before. At 

This document has been archived for historical purposes. (7/1/2016)
10 years, seropositivity was 89%, 89%, and 96% for HPV 6, 11, and 16, respectively, and 61% 

for HPV 18. Similar patterns were observed in the follow-up of other 4vHPV trials with high 

seropositivity to 3 vaccine types, and lower for HPV 18. Although some persons lost detectable 

HPV 18 antibody by cLIA in the 4vHPV clinical trials, there was no breakthrough disease. Since 

efficacy remained high, this suggests that protective levels are lower than the minimum 

detectable level by the assay or that antibodies against additional epitopes can be protective. 

When sera in these trials were retested using a total IgG assay, seropositivity to all types 

increased and seropositivity to HPV 18 reached 78% to 90%.

The following table shows 2vHPV trials with long-term follow-up for persistence of antibody: 

 

Base Trial Follow-up

Trial Participants 

(yrs)

Yrs available 

(Planned) 

Seropositive for 

16,18

Reference

2vHPV 

Immunogenicity1 

Females 10–14 10 100%, 100% Schwarz,

WSPID 2015 

2vHPV Phase II 

efficacy2

Females 15–25 9 100%, 100% Naud, Hum Vaccin Imm 2014

2HPV 

Immunogenicity3

Females 15–55 6 (10) 100%, 97% Schwarz,

BJOG 2014

The assay used for these studies was an ELISA. The longest follow-up available is 10 years 

from the adolescent immunogenicity study shown on first line. All participants in the follow-up 

remained seropositive for HPV 16 and 18. HPV 16 and 18 GMTs were 53- and 26-fold higher 

than those associated with natural infection. Similarly, in the other studies with 9 and 6 years of 

follow-up, all vaccinees remained seropositive to HPV 16 and >97% to HPV 18.

Three studies have assessed immune memory by evaluating immune response after 

administration of an additional vaccine dose after completion of the 3-dose series. In the 

monovalent HPV 16 vaccine study, this was at 8.5 years after enrollment into the base study in 

the 4vHPV trial, 5 years after, and in a 2vHPV vaccine trial 7, years after. In all studies, an 

anamnestic response was observed to the types in the original vaccination [1Rowhani-Rahbbar, 

J Clin Virol 2009; 2Olsson, Vaccine 2007; and 3Moscicki, Vaccine 2002].

Data are or will be available from trials of 2-dose schedules. The following table has results 

from 9vHPV 2-dose trial presented to ACIP in February 2016: 

This document has been archived for historical purposes. (7/1/2016)
As shown in the lighter bars, the GMTs in girls who received 2 doses at 0,6 months were noninferior and in fact higher than the titers in women (shown in red) who received the standard 3 

dose schedule for all 9 types.

 

The 9vHPV 2- versus 3-dose immunogenicity data, which was presented to ACIP in February 

2016 included data 1 month after the last dose. This trial will continue for 2 more years for 

assessment of antibody persistence. One additional dose will be given at month 36 to access 

immune memory. A separate long-term effectiveness study is being planned. 

While there are data only through 1 month after the last dose from the 9vHPV trial , there are

longer follow-up data from studies of 2vHPV and 4vHPV trials that show that the kinetics of the 

antibody response of a 2-dose schedule when given at an interval of at least 6 months is similar 

to that of a 3-dose schedule. This graphic was shown to ACIP in February 2016 and displays 

GMTs after 2vHPV vaccination in a 2-dose schedule (0, 6 months) at 9 through 14 years of age

and a 3-dose schedule at 15 through 25 years of age:

 

Follow-up in this study is through 60 months. All subjects remained seropositive for HPV 16

and 18. The lines on the graph in orange and blue are superimposed as the GMTs and kinetics 

of antibody was similar in the 2- and 3-dose groups.

This document has been archived for historical purposes. (7/1/2016)
Similarly, for 4vHPV, this graphic was shown to ACIP in February 2016 and displays antibody 

after 4vHPV vaccination after 2-doses at 9 through 13 years of age and a 3-doses at the same 

age and at 16 through 26 years of age:

 

Follow-up in this study was though 36 months. For HPV 16, the general kinetics of the antibody 

response and persistence are similar for 2 doses in girls (in black), 3 doses in girls (in red), and 

3 doses women (in green). 

In summary, there is no evidence of waning protection after a 3-dose schedule. Data are 

available through approximately 10 years for 2vHPV and 4vHPV. Longer follow-up through 14 

years is ongoing in some studies. Antibody responses are maintained over time after a 3-dose 

schedule. Data are available through approximately 10 years for 2vHPV and 4vHPV. Longer 

follow-up through 14 years is ongoing in some studies. Waning of detectable antibody to HPV 

18 by cLIA in 4vHPV vaccinees is not associated with loss of protection. Long-term protection 

data are not available yet from 2-dose trials. Antibody kinetics are similar with 2vHPV and 

4vHPV 2-dose schedules, with an interval of > 6 months between doses, in adolescents 

compared with standard 3-dose schedule in women. 

Modeling and Cost-Effectiveness of 2-Dose Vaccination Schedules

Marc Brisson, PhD

Canadian Research Chair Modeling Infectious Diseases

Professor, Université Laval

Dr. Brisson reported that a 2-dose 9-valent vaccine Phase III immunogenicity trial has been 

completed. In this trial, 2 doses of 9-valent in girls and boys 9 through 14 years old was shown 

to be as immunogenic as 3 doses in women 16 through 26 years old. The cost-effectiveness 

study question the investigators were given was:

From the societal perspective, what is the health and economic impact of switching from 

a 3- to a 2-dose schedule, in the context of an established 9-valent HPV vaccination 

program in the US? (i.e., what is the additional impact of the 3rd dose of 9-valent 

vaccine vs. 2 doses?)

The objective of the study was to evaluate the population-level effectiveness and costeffectiveness of 3- versus 2-dose 9-valent vaccination in the US. To do this, the investigators 

used a model called HPV-ADVISE. HPV-ADVISE was previously developed by Dr. Bisson’s 

This document has been archived for historical purposes. (7/1/2016)
group to answer HPV vaccination policy decisions in Canada and the US, and also has been

used in the UK and Australia. The model is an individual-based transmission-dynamic model. 

What must be understood is that this model takes into account the direct effects of vaccination 

on vaccinees, but also takes into consideration herd immunity effects. The model includes 6 

important components: 













Demographics, with individuals of different age groups

Sexual behaviour and HPV transmission between individuals

Natural history of HPV-related diseases

Vaccination 

Screening and treatment of cervical lesions and cervical cancer

Economic 

The population is open, stable, and includes individuals 10 to 100 years of age. Eighteen 

genotypes are modeled individually, including the 9 types in 9vHPV 

(6/11/16/18/31/33/45/52/58). Also included are different HPV-related diseases: Anogenital 

warts, cervical cancer (SCC and adenocarcinoma), and cancers of the anus, oropharynx, penis, 

vagina, and vulva [Brisson et al. JNCI 2016 108(1) doi:10.1093/jnci/djv282].

This is a quite complex model, but it does not mean anything unless the model is fit to data and 

parameterized appropriately. In order to do a model of predictions, the first 50 parameter sets 

were identified that fit to highly stratified data from the US. The following graphic is an example 

of the model fit to sexual behavior data from the US:

In the above example, the dots represent the data and the boxes represent the variability and 

predictions of the 50 parameter sets. Model fits also were done for HPV prevalence in women

stratified by type, age, and number of sexual partners; screening outcomes such as the 

incidence of high grade cervical lesions; and disease outcomes such as cervical cancer.

This document has been archived for historical purposes. (7/1/2016)
Once the parameters sets were identified and the model was programmed, the analysis was 

performed. The economic analysis was done from the societal perspective. The costs included 

all direct medical costs in 2013 US dollars. The main outcome was the usual outcome in health 

economics of cost per QALY gained. Future benefits and costs were discounted at 3%, the time 

horizon was 100 years, and the vaccine cost per dose assumption was $158 with administration 

costs. 

In these predictions, the investigators modeled not only the decisions of 3 versus 2 doses

prospectively, but also the policy decisions made in terms of HPV vaccination in the US. In 

these models, vaccination was begun in 2007 with a girls-only 4vHPV program. In 2011, there 

was a switch to a 4vHPV program vaccinating boys and girls. In 2015, there was a switch to a 

9vHPV program vaccinating boys and girls. This is followed by a policy question that regards 

whether to continue with a 9vHPV 3-dose program, or to vaccinate with a 9vHPV 2-dose 

program. The model prediction compares these two scenarios. To do this, vaccination 

coverage is also needed. For vaccination coverage, age-specific uptake rates were used. For 

2007-2014, observed uptake rates were used from the US National Immunization Survey (NIS). 

For 2015 onward, uptake rates were assumed to be constant at 2014 levels. 

In terms of vaccine characteristics, it is known that if efficacy and duration are similar, 2 doses 

will be cost-saving compared with 3 doses. This means that both the 2-dose and 3-dose 

schedules would be equivalent in terms the health outcomes they would prevent, but the 2-dose 

schedule would be cheaper. Therefore, the analysis examined the potential impact if 2 doses 

provided lower or equal efficacy or shorter or equal duration of protection than 3 doses. So, in 

the scenarios, the 3-dose scenario was fixed. That is, 3 doses were assumed to provide lifelong 

protection, vaccine efficacy of 95% was used, and observed vaccine coverage was used. 

Numerous 2-dose scenarios were used, including lifelong protection versus durations of 30, 25, 

20, and 15 years; a scenario of 95% versus 85% efficacy; and observed vaccination coverage 

versus a 5% to 15% percentage point increase. That is, a scenario was examined in which 

switching to a 2-dose vaccination schedule would lead to an increase in vaccination coverage.

Dr. Brisson presented two outcomes from these models: population-level effectiveness and 

cost-effectiveness. In terms of population-level effectiveness the key question was, “What 

vaccine characteristics are most important when considering reducing doses?” This refers to 

the characteristics that are most desired when switching from 3 doses to 2 doses. Sensitivity 

analyses were performed. The first assessed the impact of vaccine efficacy assumptions on the 

model predictions of effectiveness. In this scenario, it was assumed that vaccine duration is 

lifelong. The two outcomes assessed were anogenital warts and cervical cancer. For both 

vaccine efficacy scenarios, 85% and 95%, important reductions are predicted in anogenital 

warts and cervical cancer over time. The differences in population-level effectiveness between 

scenarios are quite small due to the fact that these differences in vaccine efficacy are 

counterbalanced by herd immunity effects. With respect to a 3-dose versus a 2-dose strategy, 

this suggests that if a 3-dose schedule provides 95% efficacy and in a worst case scenario a 2-

dose schedule provided 85% vaccine efficacy, there still would be very little difference in 

population-level effectiveness of 85% versus 83% respectively.

In terms of the impact of duration of vaccine protection on the model predictions, vaccine 

duration of protection has a greater impact than vaccine efficacy. If vaccine efficacy is 

presumed to be 95% in the two outcomes of anogenital warts and cervical cancer, even with 15 

years of duration of protection, there are substantial reductions in anogenital warts (53%) and 

cervical cancer (71%). It also is important to understand that once a duration of protection of 20 

This document has been archived for historical purposes. (7/1/2016)
to 25 years is reached, any benefits of increases in duration of protection beyond 20 to 25 years 

are very small. This can be shown by the following figure which shows predicted health 

outcomes prevented over 100 years with different assumptions of duration of protection with 

vaccine efficacy predicted of 95%, a population of 300 million that is similar to the US, and 

undiscounted results:

What the above figure shows is that if the duration of protection is assumed to be 15 years, 

there would be substantial reductions in all cancers related to HPV, with over 1.2 million cancers 

averted through vaccination over 100 years of duration. If the duration is 20 to 25 years, there 

would be increases in the predicted number of events that are averted, but once that range of 

vaccine protection is reached, the additional benefits are very small. In terms of 3 doses versus 

2 doses and the worst case scenario in which the 3-dose duration is lifelong and the 2-dose 

duration is 20 years, there would be very little difference in the number of cases that would be 

averted between the two scenarios. The reason this is the case is that most HPV infections are 

acquired between the ages of 17 through 30. If a vaccine is able to protect individuals during 

these key ages of peak sexual activity, it is doing a good job.

Therefore, duration of vaccine protection is quite important to population-level effectiveness. In 

terms of cost-effectiveness, this means that the key question is, “What is the cost-effectiveness 

of 2-dose and 3-dose vaccination for different assumptions of duration of protection?” In this 

analysis, 3-dose duration of protection was fixed at lifelong. The population is similar in size to 

the US. The first results regard the cost-effectiveness of 2 doses versus no vaccination. In all 

scenarios examined for 2-dose duration of protection, 2-dose schedules are cost-savings versus 

no vaccination. This means that it produces QALYs gained, or health benefits, and saves costs. 

The second result is from a comparison of the cost-effectiveness of receiving 3 versus 2 doses, 

in which 2-dose and 3-dose duration were presumed to be lifelong. In this case, the costeffectiveness of the third dose is dominated because while saving money by going to a 2-dose 

schedule, there is no change in benefits. The other question is, “What is the impact of the cost 

effectiveness of a third dose versus two doses depending on the duration of the protection of 

This document has been archived for historical purposes. (7/1/2016)
two doses?” The results suggest that if a duration of protection of 2 doses is at least 20 years, 

the cost-effectiveness ratios of giving the third dose are quite high.

Regarding the sensitivity analysis to influential variables, scenarios were assessed in which 

giving a 2-dose schedule would facilitate an increase in coverage of 5%, a 2-dose schedule 

would lead to a 15% increase in coverage, and a scenario in which 2-dose efficacy is lower than 

a 3-dose. In the base case, it was assumed that screening is cytology-based, but an 

assessment also was done in which a screening program is co-testing. Then the sensitivity 

analyses are varied to economic parameters. The first results pertaining to the costeffectiveness of 2-dose vaccination compared to no vaccination; in most of the scenarios, even 

if it is assumed that 2-dose protection lasts for 20 years, a 2-dose strategy is cost-saving versus 

no vaccination. There are certain exceptions, but even in these exceptions, the costeffectiveness ratio is very low. The second result pertains to the cost-effectiveness of 3 versus 

2 doses, in which both schedules provide lifelong protection. In all of the scenarios, the 3-dose 

schedules are dominated by 2-dose schedules except one in which it was assumed that 2-dose 

vaccine efficacy was lower than 3-dose vaccine efficacy. Even in this scenario, the costeffectiveness ratio for 3-dose vaccination is quite high. Finally, a worst case scenario was 

assessed in which 2-dose duration of protection was 20 years and 3-dose protection was 

lifelong. For most scenarios, the results vary at around $100,000 / QALY gained. In terms of 

switching to a 2-dose strategy with higher coverage, in this scenario the model predicts that if 

vaccination coverage can be increased by moving to a 2-dose strategy, this would provide equal 

or additional gains than a 3-dose strategy. Therefore, the 3-dose strategy would be dominated.

In terms of limitations, two are related to uncertainty. The first is that a duration of 2-dose and 

3-dose 9-valent vaccine efficacy and future vaccination coverage remain unknown. This is why 

duration of protection and vaccination coverage were varied in these analyses. Duration of 

protection and coverage assumptions have an important impact on conclusions. The second 

uncertainty is that screening may change in the coming years, which may modify the incidence 

of lesions and cervical cancer. While both cytology-based screening and HPV co-testing were 

modeled, the screening method did not impact the conclusions. 

This is the first effectiveness and cost-effectiveness analysis of 2- versus 3-dose vaccination 

with 9vHPV in the US or elsewhere. Thus, it is very difficult to compare the results with other 

studies. Nevertheless, the conclusions are consistent with a 4vHPV effectiveness and costeffectiveness analyses in Canada and the UK[1,2] and recently an Australian study. In these

studies, the conclusion is that 2 doses must protect for more than 20 years for the third dose to 

be cost-ineffective [1Laprise Vaccine, 2014; 2Jit BMJ, 2015].

In summary, the incremental health benefits and cost-effectiveness of a third dose of HPV 

vaccine depends upon relative duration of efficacy provided by 2 versus 3 doses. A 2-dose 

vaccination schedule is predicted to reduce HPV-burden of disease substantially and is cost 

saving if 2 doses provide protection for greater than 20 years. A 3-dose vaccination is predicted 

to have a high cost per QALY gained of greater than $118,000 compared to 2-dose vaccination, 

except when 2-dose protection is less than 20 years. A 2-dose vaccination will provide similar 

population-level health benefits to 3-dose vaccination, unless 2 doses provide shorter duration 

of vaccine protection and 2-dose schedules do not enable higher vaccination coverage. 

This document has been archived for historical purposes. (7/1/2016)
Discussion Points

Dr. Messonnier asked whether cost-effectiveness was assessed if the cost per dose in a 2-dose 

regimen is higher than the cost per dose in a 3-dose schedule.

Dr. Brisson responded that this was not assessed, and he felt uncomfortable defining a cost 

where it would be better to stick with a 2- versus 3-dose strategy. However, this can easily be 

done. There is a price at which a 2-dose strategy would not be cost-effective.

To build upon that, Dr. Bennett asked how much of the costs are actually the cost of the vaccine 

and how much are other costs (administration) such that even if the cost of the vaccine 

increased, it might still be cost-effective for 2 doses.

Dr. Brisson replied that if both schedules are equally effective, the cost per dose would have to 

increase substantially not to be cost-effective or dominate the 3-dose scenario. It is up to the 

companies, but they may vary their vaccine costs. That is a key question.

Regarding the antibody kinetics of 9vHPV versus 4vHPV, Dr. Stephens asked whether it was 

anticipated that there would be equivalent 9vHPV data at least for the types that are in both 

vaccines.

Dr. Markowitz replied that this is the assumption since the monovalent, 2vHPV, and 4vHPV 

trials have all shown the same pattern of an antibody peak one month after the last dose 

followed by a plateau. The data available are only for one month past the last-dose, but more 

data should be available soon that would include a later time point to assess whether that is 

true. She called upon a representative from Merck to address this.

Dr. Luxembourg (Merck) responded that additional data would be available for Months 25 and 

36 by the end of 2017. Regarding whether the 9-valent has similar immunogenicity, so far for all 

studies measured, no substantial differences have been found in immunogenicity between the 

vaccines. Therefore, it is a reasonable to assume that it will be the same.

Dr. Kempe acknowledged that duration of protection is the most important aspect of modeling, 

but the other thing that they tried to vary was the percentage of potential increase in 

immunization. She wondered whether data are available from the countries that have made the 

switch from 3 to 2 doses and if changes in uptake greater than 15% have been observed.

Dr. Markowitz responded that many of the countries that have switched have school-based 

vaccines so the impact of changing from a 3-dose to a 2-dose schedule on coverage might not 

be relevant to the US situation. An effort is being made to acquire data to find out what is 

occurring. Some countries in Europe have clinic/primary care-based vaccination programs and 

there may be some data available from those programs.

Regarding vaccination coverage and trends over the 100 year time period, Dr. Thompson 

(NVAC) wondered whether it would be cost-effective to give 9vHPV vaccine to those who 

already received 2vHPV or 4vHPV.

This document has been archived for historical purposes. (7/1/2016)
Dr. Brisson replied that in terms of the assumptions regarding coverage based on observed 

rates, from 2000 through 2014, they used the percent of coverage with 3 doses only. That was 

predicted into the future, so for 2015 onward those would be the assumptions if the uptake rates 

remain the same. When the 2-dose schedule was modeled without any increase in coverage, 

the same assumptions about coverage were used. When a predicted increase in vaccination 

coverage was modeled with a 2-dose program, it was cost-saving. Regarding revaccination of 

those previously vaccinated with 2vHPVt and 4vHPV, Dr. Chesson has published a paper on 

that in which this question was assessed with 3 doses with the HPV-ADVISE model and with a 

CDC model. The cost-effectiveness ratios were quite high. In terms of the results with 2 doses, 

a sensitivity analysis was performed.

Dr. Chesson added that the result for 2 doses was approximately $100,000 per QALY to 

revaccinate.

Dr. Reingold suggested that if by the October 2016 ACIP meeting they were able to use this 

information to shift from a 3- to a 2-dose strategy, perhaps it would be possible to model 

pneumococcal conjugate vaccine doses shifting from 4 to 3.

HPV Vaccine Effectiveness Studies 

Sara Oliver, MD, MSPH

EIS Officer, Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Oliver reminded everyone that to inform policy decisions, current evidence is being reviewed 

for 2 doses of HPV vaccine, including evidence regarding immunogenicity, efficacy, and postlicensure effectiveness. A previous presentation to ACIP in February 2016 reviewed data from 

HPV vaccine 2-dose immunogenicity studies and presented data from the major efficacy 

studies. During this session, Dr. Oliver presented a systematic review of vaccine efficacy and 

effectiveness for 2 doses. She began by searching for studies on HPV vaccine effectiveness, 

identifying 930 papers on vaccine impact or effectiveness. Studies were selected if they 

evaluated effectiveness by number of doses. Thirteen papers were reviewed that discussed

vaccine effectiveness with 2 doses. The WG reviewed these studies in detail previously. 

During this session, Dr. Oliver presented studies by vaccine and outcomes evaluated. She 

described all 13 studies, and showed detailed data for studies evaluating outcomes by timing of 

interval between Dose 1 and Dose 2.

To better understand the background of the studies presented, it is worth nothing that there are 

many methodological challenges to using post-licensure effectiveness studies within the context 

of a 3-dose program to evaluate 2-dose effectiveness. Most vaccinees received 2 doses at a 

0,1 or 0,2 month interval. In addition, many studies were conducted during a catch-up 

vaccination period, meaning that many females were vaccinated at ages older than current 

recommendations. Also, the partially vaccinated population is different from those fully 

vaccinated, potentially having implications for exposure to HPV prior to vaccination and different 

sexual risk status. However, in spite of these challenges, Dr. Oliver presented an overview of 2-

dose effectiveness studies for a complete review of the evidence and in order to highlight their 

limitations with interpretation. No studies on 2-dose effectiveness of 9vHPV have been 

published to date, since 9-valent was licensed only recently.

This document has been archived for historical purposes. (7/1/2016)
For 4vHPV, 8 studies have been published on effectiveness by number of doses: 1 study 

evaluating effectiveness with regards to HPV infection (Sankaranarayanan Lancet Oncol 2016), 

3 studies evaluating genital warts (Herweijer JAMA 2014, Dominiak-Felden PLOS ONE 2015, 

and Blomberg Clin Infect Dis 2015), and 4 studies evaluating cervical pre-cancers (Hofstetter 

JAMA Peds 2016, Crowe BMJ 2014, Gertig BMC Medicine 2013, and Brotherton Papillomavirus 

Res 2015). 

The Sankaranarayanan study was a 2- versus 3-dose trial conducted in India. Immunogenicity 

data was discussed at the previous ACIP meeting in February. Infection outcomes also were 

reported, evaluating incident and persistent cervical HPV infections. The study was designed 

as a cluster-randomized trial, but was stopped prior to completion, so it was analyzed as an 

observational cohort study. Subjects were randomized to receive 3 doses or 2 doses at a 0,6

month interval. In addition, since the trial was stopped early, some participants received 2 

doses at a 0,2 month interval or 1 dose. There were no persistent infections in any group. 

Overall, 2 doses at a 0,6 month interval was similar to 3 doses. The primary limitation with 

interpretation remains that the study was designed as a randomized trial that was analyzed as a 

cohort study. Because randomization was disrupted, there could be differences between 

groups as well.

Three studies evaluated 4vHPVeffectiveness for genital warts by number of doses (Herweijer, 

Dominiak-Felden, and Blomberg). Each study had a slightly different study population, but all 

were designed as population-based retrospective cohorts. The conclusion of all 3 studies was 

that maximum vaccine effectiveness was noted with 3 doses. However, all studies evaluated 

effectiveness from those partially vaccinated in the setting of a 3-dose recommendation. The 

partially vaccinated cohort was different than the fully vaccinated cohort in that they were 

generally older at the time of vaccination and most received 2 doses at a (0,2 month) interval. 

The Blomberg study evaluated 2-dose effectiveness for genital warts by interval. As the time 

between Dose 1 and Dose 2 increases from 2 to 6 months, the incidence rate ratio for 2 versus

3 doses approaches 1, meaning the effect of 2 doses when given at a longer interval, 

approaches 3 doses. This is the only effectiveness study to clearly demonstrate this effect by 

interval. However, while the findings are of interest, the authors point out that a limited number 

of vaccinees received 2 doses at the longer interval, compared with those who received the 

shorter interval.

Four studies assessed 4vHPV effectiveness for cervical pre-cancer by number of doses 

(Hofstetter, Crowe, Gertig, and Brotherton). One was a case-control study and the other 3 were 

retrospective cohort studies. All 4 studies concluded that maximum vaccine effectiveness was 

found with 3 doses. However, as before, all evaluated a partially vaccinated population in the 

setting of 3 recommended doses. Again, the partially vaccinated cohort was different than the 

fully vaccinated cohort in that they were generally older at time of vaccination and had potential 

indicators of earlier sexual exposure, including younger cervical screening, vaccinated at a 

family planning clinic, or sexually transmitted infection (STI) screening. Most received 2 doses 

at a (0,2 month) interval.

This document has been archived for historical purposes. (7/1/2016)
The Brotherton study from Australia assessed risk reduction for cervical pre-cancer by number 

of doses and interval. This table shows hazard ratios by number of doses and timing of the 2-

dose interval:

Vaccination Time between doses Hazard Ratio

3 doses - 0.71 (0.64–0.80)

2 doses <6 months 1.25 (1.03–1.51)

2 doses ≥6 months 1.05 (0.72–1.55)

For 2 doses, an interval greater than or equal to 6 months had a slightly lower hazard ratio 

compared to an interval less than 6 months, but neither ratio was significantly lower than the 

unvaccinated population. However, in this particular study, the partially vaccinated females 

were older at vaccination, younger at first cervical screening, and had a lower socioeconomic 

status (SES). The numbers were small in the 2-dose cohort, with less than 20% of vaccinees 

receiving 2 doses, and less than 5% receiving 2 doses at least 6 months apart.

Moving now to 2vHPV, there have been 5 studies evaluating vaccine effectiveness or efficacy, 4 

evaluating HPV infection (Kavanagh BJC 2014, Cuschieri BJC 2016, Kreimer JNCI 201, and 

Kreimer Lancet Oncol 2015), and 1 evaluating cervical pre-cancers (Pollock BJC 2014). 

Two studies evaluated 2vHPVeffectiveness for HPV infection by number of doses, both 

conducting a cross-sectional study using residual cervical screening samples and registry data 

(Kavanagh and Cuschieri). In the first study, no statistically significant risk reduction was found 

with 2 doses compared to the unvaccinated population. However, the study noted that they 

were not powered to detect a difference for two doses. The second study was conducted, overselecting for those who were partially vaccinated. An impact was then found for 2 doses, but 

still less than the impact observed for those fully vaccinated. However, Scotland had a 3-dose 

recommendation at the time both studies were conducted, and the partially vaccinated females 

were older at the time of vaccination than those fully vaccinated, and primarily received a 0,1 

month interval.

Two published studies evaluated 2vHPV efficacy by number of doses, both as a post-hoc 

analyses of clinical trials (Kreimer 2011 and Kreimer 2015). The first study was a post-hoc 

analysis of the Costa Rica Vaccine Trial, evaluating those who did not receive all 3 doses. The 

second analysiscombined the data from both the Costa Rica Vaccine Trial and the PATRICIA 

trial, again evaluating those partially vaccinated. In both studies, a high efficacy was found with 

1, 2, and 3 doses. However, all subjects were initially randomized to receive 3 doses of HPV 

vaccine, and a small proportion were unable to complete the series, most commonly due to 

pregnancy.

This document has been archived for historical purposes. (7/1/2016)
A sub-analysis from the 2015 Kreimer paper, only including data from the Costa Rica Vaccine 

Trial, evaluated efficacy by timing of a second dose. This table shows vaccine efficacy by 

number of doses and timing of the 2-dose interval:

Vaccination Interval Vaccine efficacy (95% CI)

3 doses* — 77.0% (74.7–79.1%)

2 doses 1 month 75.3% (54.2–87.5%)

2 doses 6 months 82.6% (42.3–96.1%)

For comparison, the efficacy for 3 doses is shown. Of note, the 3-dose cohort includes 

participants from both the Costa Rica Vaccine Trial and the PATRICIA trial. High efficacy was 

seen for both a 1-month and 6-month interval, with an estimate slightly higher for a longer 

interval. However, a small percentage of study participants received the second dose after 6 

months, providing wide confidence intervals for the estimate.

A final study evaluated 2vHPVeffectiveness for cervical pre-cancers by number of doses

(Pollock). Only females who had received a colposcopy were included in this analysis. No risk 

reduction was found with 2 doses compared to those unvaccinated. However, the partially 

vaccinated females were older and more likely to have received their vaccination after 

graduation from school. Most were vaccinated a 0,1 month interval and, in the setting of a 3-

dose recommendation, only a small proportion of the population received 2 doses.

In summary, 13 studies evaluated 2-dose effectiveness. Of these, 3 were post-hoc analyses of 

clinical trials and 10 were post-licensure effectiveness studies evaluating partially vaccinated

individuals in settings of a recommended 3-dose schedule. Additionally, 4 studies included 

evaluations of at least a 0,6 month interval.

 

In conclusion, 3 studies found similar outcomes for 2 doses compared to 3 doses, and all 3 of 

those studies were post-hoc analyses of clinical trials. Ten studies found 2 doses were not as 

effective as 3 doses. However, it is important to note that all 10 were post-licensure 

effectiveness studies performed within settings of a recommended 3-dose schedule, where 

most received a 0,1 or 0,2 month interval. Persons who only received 2 doses were different 

from those completing the series. Several studies found the partially vaccinated females to be 

older, of lower SES, or to have earlier cervical screening—a potential indicator for earlier onset 

of sexual activity. All of those factors have implications for exposure to HPV prior to 

vaccination. There were 4 studies evaluated a 0,6 month interval compared to a shorter 

interval. Of those four studies, 1 showed a longer interval was more effective. The other 3 

studies suggest that a longer interval could impact vaccine effectiveness, but statistical 

significance was not always tested or achieved. As mentioned previously, there are many 

methodological challenges to using post-licensure effectiveness studies within the context of a 

3-dose program to evaluate 2-dose effectiveness. Data from these post-licensure effectiveness 

studies may not be directly applicable to the currently policy question of a 2-dose 

recommendation due to differences in age at vaccination, the interval between the 2 doses, and 

the population in the studies receiving 2 doses compared to those who received 3 doses. 

These important factors have impacted the studies included in GRADE, which are addressed in 

the next presentation.

This document has been archived for historical purposes. (7/1/2016)
GRADE for 2-Dose Schedules

Elissa Meites, MD, MPH

Medical Epidemiologist

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Meites discussed the GRADE process for 2-dose schedules of HPV vaccine. During this 

and the February 2016 ACIP meeting, there were discussions of various components of the 

GRADE process. Before making an ACIP recommendation and assigning a GRADE category, 

the steps of this evidence-based method are to: 

















Develop policy questions 

Consider critical outcomes 

Review and summarize evidence of benefits and harms 

Evaluate the quality of evidence 

Assess population benefit 

Evaluate values and preferences 

Review health economic data 

Offer considerations for formulating recommendations 

The WG’s main policy question was, “Should 2 doses of any HPV vaccine be recommended for 

9-14 year-olds?” Given anticipated changes in availability, each HPV vaccine was considered 

separately. The population of interest was girls and boys aged 9 through 14 years. The 

intervention was 2 doses of HPV vaccine, separated by 6 to 12 months. The comparison was 3 

doses of HPV vaccine on a standard schedule, among women in the age group in which 

vaccine efficacy has been demonstrated against infections and histopathological lesions

associated with HPV vaccine types. This was done in immunobridging studies. Note that 

exploratory analyses comparing groups in the same age range of 9 through 14 years were 

considered supplemental data in this presentation. The main outcome of interest was 

immunogenicity or antibody response to vaccine-type HPV.

Most of the studies in this presentation were immunobridging studies, because the minimum 

threshold level of HPV antibodies required for clinical protection has not been established and 

might vary depending on the assay. Data from clinical trials suggest that this minimum level of 

antibody needed for protection could be below that which is detected by current assays. 

Immunobridging studies are used to compare immunogenicity in a group of interest (for 

example, those aged 9 through 14) with a comparison group in which efficacy has been 

demonstrated in clinical trials (for example, those aged 16 through 26). Non-inferiority criteria 

are met when the lower bound of the 95% confidence interval for the ratio comparing the two 

groups is not less than a pre-set value such as 0.5. Immunobridging studies are the basis upon 

which HPV vaccines were originally licensed in the US for use in 9 through 15-year-olds.

In terms of outcomes relevant to HPV vaccination as determined by the WG, immunogenicity is 

an early measurable effect of HPV vaccination, and a surrogate marker for prevention of other 

important outcomes such as HPV infections, genital warts, or condylomas; and critical outcomes 

including HPV-associated pre-cancers and cervical, oropharyngeal, anal, and other cancers. 

Immunogenicity outcomes are included in the evidence profile for GRADE. These include the 

following:

 

This document has been archived for historical purposes. (7/1/2016)






Rates of seroconversion, which means having any detectable vaccine-type antibody after 

vaccination

GMTs, which quantify antibody levels

Antibody avidity, which measures how strongly antibody binds to its antigenic target 

Data on other important outcomes, including the efficacy studies reviewed in the previous 

presentation by Dr. Oliver, were considered by the WG, but were not included in GRADE 

because they did not include data on the relevant dosing interval or age range specified in the 

policy question. To date, no data are available on the later outcomes listed as critical.

For evidence retrieval, the WG conducted a systematic review of studies from PubMed and 

Clinicaltrials.gov published between 2006, when HPV vaccine was first licensed in the US, and 

June 17, 2016. Efforts were made to obtain unpublished or other relevant data. Initial search 

terms included both:





“HPV” and “vaccine,” or “HPV vaccine,” or “papillomavirus” and “vaccine,” or “papillomavirus 

vaccine,” AND 

“2-dose” or “2 doses” or “two-dose” or “two doses”

Relevant studies included human subjects, primary data, and data relevant to the outcomes 

shown above for 9-valent, quadrivalent, or bivalent HPV vaccines.

The search identified 117 publications listed in PubMed. Nine relevant publications were 

reviewed in detail, and six immunogenicity studies that were non-redundant were included in the 

evidence tables. The other 108 were excluded as 31 were not primary data (reviews, 

editorials); 57 had other outcomes (coverage, knowledge/preferences, cost-effectiveness); and 

19 assessed relevant outcomes, but did not report results by timing of doses administered or 

number of doses in the age group of interest. In addition, 14 studies were identified that were 

registered on clinicaltrials.gov, including 1 additional relevant study with unpublished data. This 

was the 9-valent vaccine 2-dose trial that was presented by the manufacturer during the 

February 2016 ACIP meeting. All of the relevant immunogenicity studies and additional data 

included in GRADE were previously presented to ACIP during the February meeting.

Initial evidence types in GRADE are either a type 1 for RCTs or Type 3 for observational 

studies. For immunobridging studies, the main analyses are considered observational since it is 

not possible to randomize participants to an age group even if these studies are considered 

strong evidence. Therefore, an evidence type of 3 is the highest possible for this type of study.

 

For the GRADE evaluation of 9-valent HPV vaccine, the policy question was, “Should 2 doses 

of 9-valent vaccine be recommended routinely for 9 through 14 year-olds?” Regarding the 

characteristics of included studies, one immunobridging study funded by the manufacturer that 

was submitted to FDA and was presented to ACIP in February 2016. This study compared 2 or 

3 doses of 9-valent vaccine in girls and boys 9 through 14 years of age with 3-doses given to 

women 16 through 26 years of age. The two doses were given at an interval 0 and 6 months 

apart, or 0 and 12 months apart, plus or minus 4 weeks. The main immunogenicity outcomes 

from the study were seroconversion and GMTs.

This document has been archived for historical purposes. (7/1/2016)
For seroconversion, in each group of vaccinees at least 97.9% had seroconverted to all 9-valent 

vaccine types at 4 weeks post-last dose. When comparing 2-dose girls-and-boys to 3-dose 

women, noninferiority criteria were met for all 9-valent vaccine types regardless of whether the 2 

doses were administered at a 0,6 or a 0,12 interval, and whether girls and boys were assessed 

separately. GMTs for 9-valent vaccine types were significantly higher in the 2-dose girls and 

boys compared with the older controls. For the finding of non-inferior immunogenicity with 2 

doses of 9-valent HPV vaccine in girls and boys compared with 3 doses in a group in which 

clinical efficacy has been demonstrated, this immunobridging study is considered observational 

and receives an initial evidence level of 3. Evidence type was not downgraded for risk of bias, 

inconsistency, indirectness, imprecision, or any other considerations, giving a final evidence 

type of 3.

For the sake of transparency, Dr. Meites mentioned additional analyses from this study that 

compared 2-doses in girls-and-boys with 3 doses in the same age group. These analyses are 

considered exploratory or supplemental because the comparison was not with the group in 

which efficacy was demonstrated in the clinical trials and, therefore, falls outside of the 

parameters of the study question. For seroconversion, in the first row, at least 99.2% in all the 

2-dose groups seroconverted to all 9-valent vaccine types at 4 weeks post-last dose. GMTs

were statistically lower in the 2-dose group for some HPV types at 4/9 for the 0,6 month group 

and 1/9 in the 0,12 month group, although formal non-inferiority comparisons were not 

performed.

For quadrivalent HPV vaccine, the policy question was, “Should 2 doses of quadrivalent vaccine 

be considered adequate vaccination for 9 through 14 year-olds?” In terms of the characteristics 

of the included studies, two published studies were identified. Both were publically-funded 

immunobridging studies, one from Canada (Dobson) and one from Mexico (Hernandez-Avila). 

These studies compared girls in the 9 through 13 year-old age range with women in the age 

group in which efficacy was demonstrated in the clinical trials. In both studies, the 2-doses were 

given at an interval of 0, 6. The main immunogenicity outcomes from these studies were 

seroconversion and GMTs. In both studies, among all vaccinees at least 97.1% were 

seropositive to all quadrivalent vaccine types at 7 months in all groups. For GMTs, both studies 

found that when comparing 2-dose girls to 3-dose women, noninferiority criteria were met for all 

four quadrivalent vaccine types through 36 months, and GMTs for 9-valent vaccine types 

usually were significantly higher in the 2-dose groups. For the finding of non-inferior 

immunogenicity with 2 doses of quadrivalent HPV vaccine in girls compared with 3 doses in a 

group in which clinical efficacy has been demonstrated, these two immunobridging studies are 

considered observational, and received an initial evidence level of 3. Evidence type was not 

downgraded, giving a final evidence type of 3.

Supplemental analyses of same-age comparisons from these studies were presented for 

completeness, although they were not included in the GRADE analysis. For seroconversion, at 

least 97.2% in all the 2-dose groups were seropositive to all quadrivalent vaccine types at 

month 7. For GMTs, the two studies had similar findings in that GMTs to quadrivalent vaccine 

types were high in all vaccinees, but relatively lower in the 2-dose girls compared with the 3-

dose girls, even though noninferiority criteria usually were met. One study showed that 

noninferiority was lost for HPV 18 by month 18, and also HPV 6 by month 36. However, the 

other study showed that noninferiority was not lost by the end of the study at month 21 for any 

of the quadrivalent vaccine types.

This document has been archived for historical purposes. (7/1/2016)
For bivalent HPV vaccine the policy question was, “Should 2 doses of bivalent vaccine be 

considered adequate vaccination for 9 through 14 year-olds?” Regarding the characteristics of 

the included studies, there were 4 published studies. There were 3 immunobridging studies 

from various countries (Romanowski, Puthanakit, Lazcano-Ponce), and 1 observational 

laboratory study (Boxus). These studies compared girls in the 9 through 14 age range with 

women in the age group in which efficacy was demonstrated in the clinical trials. Interventions 

included either 2 doses at an interval of 0,6 months or 0,12 months versus 3 doses on a 

standard schedule. Main outcomes for the three immunobridging studies were seroconversion 

and GMTs, and the laboratory study assessed antibody avidity.

In all three immunogenicity studies, 100% of vaccinees seroconverted to both bivalent vaccine 

types and were seropositive through Month 60. For GMTs, all three studies found that when 

comparing 2-dose girls to 3-dose women, noninferiority criteria were met for both bivalent 

vaccine types through 60 months, and GMTs for 9-valent vaccine types were higher in the 2-

dose groups. For antibody avidity (bivalent vaccine), there were no differences in avidity index, 

suggesting similar quality of antibody response in 2-dose versus 3-dose recipients. For the 

finding of non-inferior immunogenicity with 2 doses of bivalent HPV vaccine in girls compared 

with 3 doses in a group in which clinical efficacy has been demonstrated, these four studies are 

considered observational and received an initial evidence level of 3. Evidence type was not 

downgraded, giving a final evidence type of 3.

Again for completeness, same-age comparisons from the graded studies in this section were 

presented. Two studies had both a 2-dose and a 3-dose arm for girls in the same age group. 

For seroconversion in two studies, 100% of vaccinated girls seroconverted to both bivalent 

vaccine types and were seropositive through month 60 (Romanowski, Lazcano-Ponce). For 

GMTs, one paper provided GMT results for both 2-dose girls and 3-dose girls (Lazcano-Ponce). 

At month 21, GMT ratios were lower in the 2-dose group, but noninferiority criteria were met for 

both bivalent types.

In addition to benefits, the workgroup also discussed potential harms. For AEs, the safety 

profile has been well-established for HPV vaccines, and SAEs are extremely rare. Dr. Meites 

reiterated that in the 9-valent vaccine trial presented to ACIP and included in GRADE earlier, 

there were no serious vaccine-related adverse events. In 2-dose cohorts, the incidence was 

zero among 883 participants, and in 3-dose controls it was zero among 616 participants. Any 

potential AEs following a dose of vaccine, for example injection site reactions, can be expected 

to be reduced when fewer doses are given. No data suggest that AEs would increase with 

fewer doses.

In summary, for 2 doses of HPV vaccine in girls or boys age 9 through 14 years, compared with 

3 doses of HPV vaccine in a group in which clinical efficacy has been demonstrated, data were 

available on immunogenicity outcomes for 9-valent, quadrivalent, and bivalent HPV vaccines. 

All found evidence of non-inferior immunogenicity with 2 doses, and the overall evidence type is 

3. Considerations for formulating recommendations for 2-doses of HPV vaccine include 

balances between benefits and harms, evidence type for benefits, values, and costeffectiveness. In terms of benefits and harms, benefits are non-inferior and harms are reduced 

compared to 3 doses. If benefits are expected to be similar and the potential AEs are lower, 

then the balance of benefits over harms is greater. The evidence type for benefits was 

evidence type 3. Regarding values, the WG placed a high value on programmatic 

considerations, as well as prevention of outcomes due to HPV vaccine types. As discussed by 

Dr. Brisson, 2-doses are likely cost-effective compared to 3 doses. 

This document has been archived for historical purposes. (7/1/2016)
Discussion Points

As a matter of principle, Dr. Sun (FDA) asked whether when considering potential harm, the 

potential for infection during the period after the first dose before the second dose was 

considered. All of the immunogenicity studies compared post-six month dose. Theoretically, if 

one acquired infection during that interval, that could represent potential harm. In this particular 

case, the immunogenicity of the vaccine is probably so high that this is not an issue. 

Nonetheless, that would be important to consider as a potential harm in any reduced dose 

strategies. One can look at the boost response when the second vaccine is given at 1 month 

versus at 6 months and could compare it with the quality of the anamnestic response.

Dr. Meites responded that in terms of how the WG assessed harms, several studies have 

evaluated any reported AEs after each dose—so by timing and dosing of the different vaccines. 

Comparing after dose 1, dose 2, dose 3, there was not an appreciable difference. Dr. 

Markowitz added that the recommended age for vaccination in the US is at 11 or 12 years. 

Ideally, people would be vaccinated before risk of exposure. The 2-dose recommendation 

would be exclusively in the younger age group based on the data being submitted to the FDA. 

This is a strong argument for vaccinating at the younger age.

Recommendation Options

Lauri Markowitz, MD

National Center for Immunization and Respiratory Diseases 

Centers for Disease Control and Prevention

Dr. Markowitz presented the draft proposed recommendations for a 2-dose schedule. She 

emphasized that these were general recommendations rather than specific wording, and that 

they do not include specifics on minimum intervals, special conditions, or precautions. This is 

simply a general outline of what the WG has been considering. The WG’s proposed 

recommendation for routine vaccination is that: 





ACIP recommends routine HPV vaccination at age 11 or 12 years*

A 2-dose schedule is recommended+. The second dose should be administered 6 to 12 

months after the first dose. 

*Vaccination series can be started at age 9 years +A 3-dose series can be given (0, 1-2, 6 months) 

The text in blue indicates issues for further discussion. For example, the interval between 

doses could be a range as stated here, specific intervals, or just a lower minimum interval. 

Furthermore, the specific range might change depending what is in label. The other text for 

discussion is the statement about an optional 3-dose series, so that although the 

recommendation is for a 2-dose schedule, a 3-dose series could be given at the discretion of 

the provider.

Consistent with ACIP’s current recommendations, the draft includes a recommendation for 

vaccination through 26 years of age for females and 21 years of age for males if not previously 

vaccinated. For this recommendation, there would be different recommendations for those who 

initiate vaccination before or after their 15th birthday as follows:

This document has been archived for historical purposes. (7/1/2016)






Vaccination is also recommended for females through 26 years and for males through 

21 years not previously vaccinated

For persons initiating vaccination before their 15th birthday, ACIP recommends 2 doses 

of HPV vaccine.* The second dose should be administered 6 to 12 months after the first 

dose.

For persons initiating the vaccination series after their 15th birthday, ACIP recommends 3 

doses of HPV vaccine. The second dose should be administered 1 to 2 months after the 

first dose and the third dose 6 months after the first dose (0, 1-2, and 6 month schedule).

*A 3-dose series can be given (0, 1-2, 6 months)

Again, the text in blue indicates wording for further discussion related to how to state the interval 

between doses and whether a 3-dose series should be an option for those initiating vaccination 

before the 15th birthday.

The following wording pertains to what would be considered adequate vaccination for those who 

started vaccination in the past.

 

If vaccination was initiated before the 15th birthday:



– 

– 

– 



– 

– 

– 



Persons who started the HPV vaccination series with 9vHPV, 4vHPV or 2vHPV and

received 2 doses > 6 months apart: are considered adequately vaccinated

received 2 doses < 6 months apart: should receive a third dose > 6 months after 

dose 1

received 1 dose: should receive a second dose > 6 months after dose 1

If vaccination was initiated on or after the 15th birthday:

Persons who started the HPV vaccination series with 9vHPV, 4vHPV or 2vHPV and 

received 3 doses with the third dose > 6 months after dose 1: are considered 

adequately vaccinated

received 2 doses: should receive a third dose > 6 months after dose 1 

received 1 dose: should complete a 3-dose series (0, 1-2, 6 months)

The draft recommendation for special populations is:

For immunocompromised patients of any age, including those with HIV infection, ACIP 

recommends 3 doses of HPV vaccine (0, 1-2, 6 months)

This document has been archived for historical purposes. (7/1/2016)








– 

– 

Dr. Markowitz posed the following issues for discussion:

General support for a 2-dose recommendation 

Whether ACIP recommends “HPV vaccine” or “9vHPV” since that will be the only 

vaccine available going forward in the US

Recommendations for those starting series before 15th birthday

Whether ACIP feels that it will be helpful to specify intervals between doses (0, 6 

months or 0, 12 months), to have a range of the interval (6 to 12 months), or a 

minimal interval (at least 6 months)

If a 2-dose schedule is recommended, should there be an option for a 3-dose 

schedule?

Discussion Points

Dr. Reingold said he assumed that if there were an option for a 3-dose schedule formally, that 

would have implications in terms of who would pay for it or whether it would be covered by a 

program or insurance company. He asked for further insight into what the rationale would be for 

continuing to include a 3-dose schedule option.

Dr. Markowitz replied that while discussion regarding this issue is ongoing, it is partially a legacy 

issue, since a 3-dose scheduled has been recommended. Also, some practices may be 

vaccinating a wide age range and may give a 3-dose schedule to some individuals 

inadvertently, and would want that to be covered. Some individuals may want a 3-dose 

schedule. While it was not a unanimous consideration among the WG members, some 

members felt strongly about including this option.

Dr. Riley said she was confused with the 3-dose option as well. She asked for clarity regarding 

whether this meant an option for a 3-dose schedule in those less than 15 years of age. She 

wondered whether this made sense for some medical reason. Using HIV as an example, she 

asked whether that would be a patient for whom there would be concern about the immune 

response.

Dr. Markowitz confirmed that this was what was for those less than 15 years of age at the time 

of vaccine initiation. Some WG members wanted a 3-dose option for this group. However, the 

recommendation for 3-doses would remain for immunocompromised persons, including those 

with HIV infection for all age groups.

 

As a Program Manager, Dr. Moore weighed in on the interval suggestions. She would not 

include the “at least 6 months” with the open end, because it makes it very hard for any registry 

to calculate whether a patient is overdue for something. With just “at least 6 months” they would 

never be overdue theoretically. Understanding the antibody data, she liked the range of 6 to 12 

months rather than being prescriptive with 0 to 6 or 0 to 12 because from a practice standpoint, 

a 6-month interval will work easily into the schedule for others having their first vaccine at their 

11-year old visit and their next vaccine at their 12-year old visit. Depending upon the setting, 

both are reasonable and the 6 to 12 month range offers that flexibility.

Dr. Kempe agreed that the 6 to 12 month range offers clinicians the option with individual 

patients. Some patients are 11 years old who are clearly far away from sexual activity for whom 

it might make much more sense to wait a year. That might be much easier for programmatic 

This document has been archived for historical purposes. (7/1/2016)
reasons, so she really liked that. With regard to Immunization Information Systems (ISS), she 

requested further information on whether having a range is problematic for that.

Dr. Moore replied that there are other vaccines that have ranges for when doses are due, so 

that is programmable.

Dr. Finley (AIM) added that the range of 6 to 12 months would be very helpful, and it is in all of 

the forecasters so it would work well for them.

Dr. Walter noted that many children in his practice present on yearly intervals and are currently 

receiving their vaccine that way.

Dr. Schaffner (NFID) asked whether they may infer that because of what had been said about 

people who have completed their immunization series, ACIP would not be considering at this 

time the question of whether the series was completed with a 2vHPV or 4vHPVand if patients 

who had completed either of those series should receive 9vHPV. He also made a plea for 

simplification of the adult immunization schedule, perhaps considering the upper age limit of 

women and men and making them the same.

Dr. Markowitz responded that the WG has been dealing exclusively with reviewing the evidence 

for 2 doses since February and has not revisited some of the issues that have arisen previously. 

They are aware of the upper age range differing for males and females, and can further 

consider this issue. They have not addressed again the issue of the additional vaccination with 

9vHPV. 

Dr. Kempe requested people’s perspective on “HPV vaccine” or “9vHPV”. ACIP has been 

careful not to specify specific vaccines in the past. In this case, two of the vaccines are 

essentially being phased out. She personally could foresee a problem with having the 

specificity. If people come in from other countries, there may be confusion about whether they 

received the correct vaccine. Some members of the WG felt that it should be specified. She 

said she would like to hear from anyone who felt that it should be specified and why.

Dr. Lett (CSTE) agreed with not specifying. The concern is that it will raise questions about 

revaccination, which it seemed the WG did not wish to address at this point.

Dr. Belongia agreed, given that as of the end of the year, only 9vHPV would be available in the 

US.

Dr. Moore agreed with Drs. Lett and Belongia. Many individuals come in from other countries, 

and they do not want to cause confusion in the schedule. No evidence has been presented to 

raise concern about the other vaccines.

Dr. Reingold asked whether this was relevant because of requirements to have had the vaccine 

to attend school. He was not clear why others entering the country were relevant in terms of 

whether they received a different HPV vaccine with regard to what ACIP specifies.

Dr. Moore clarified that they were saying it is not relevant. The preference is to say “HPV 

vaccine” rather than specifying 9vHPV.

This document has been archived for historical purposes. (7/1/2016)
Dr. Bennett thought the concern was that if a practitioner was assessing someone’s vaccination 

status, if the recommendation is 9vHPV, if the person might be perceived as being unimmunized if they received 2vHPV or 4vHPV. That was not what was intended.

Regarding the 6- to 12-month span in terms of the second dose, Dr. Middleman (SAHM) 

reminded everyone that the Youth Risk Behavior Survey (YRBS) indicates that approximately 

25% of adolescents have had sex by 9th Grade. She thought they should keep that in mind 

when considering a 6 to 12 month window in terms of whether people may have intercourse 

before the series is completed. 

Dr. Wexler (Immunization Action Coalition) said that if ACIP decided to use “9vHPV,” she 

recommended use of HPV9, HPV4, HPV2 as 9vHPV has posed difficulties in terms of the use of 

abbreviations in tools and informational pieces. They have emailed CDC about this issue. 

HPV9, HPV4, HPV2 would be consistent with PPSV23 and PCV13. Putting the number 

afterward is less awkward in terms of writing / space.

Dr. Markowitz noted that the feedback received suggested that only “HPV” should be used in 

the recommendation.

My Name is Deborah Sullivan. I live in Little Silver New Jersey. I have been an oncology nurse 

in New York City for 25 years. My family sits on the board of many NY hospitals and have 

floors named after them. I would like my voice to be heard at the June 22nd meeting. I have 

four children, all of whom have been fully vaccinated. Although one of my daughters was 

diagnosed with type 1 diabetes at the age of 5, and it was speculated at the time it could have 

been triggered by the R part of the MMR. Anyway, I still continued to vaccinate my children with 

the understanding there is always a risk of reaction. However, in the summer of 2015, my 

daughter received the HPV vaccine Gardasil and in less than 24 hours she was on the floor 

having what looked to be a panic attack. This occurred for three days and then tonic clonic 

seizure like activity began. I won't get into the whole story, but my daughter now has POTS, a 

cardiac arrhythmia ventricular tachycardia as well as joint pain, brain fog, 

repeated throat infections, and severe new allergies. My other daughter as well was affected 

and had all of the same symptoms with added vomiting and diarrhea. This is my type 1 diabetic 

daughter who received two shots all symptoms became worse after second shot, including 

debilitating headaches.

This is what I want to be heard!! I understand the benefit of vaccines. I also understand there is 

potential risk. What I don't understand is WHY when someone is affected that no doctors will 

help and the government does all it can not to payout to the victims.

The anti-vaccine people get a bad wrap because they have had to go out and fend for

themselves with no help from doctors, so now they go out and promote "don't give vaccines". 

They know their child was affected, but because the link can't be proven, it is just dismissed. IF 

the government would take measures to set up protocols to treat victims and then try to change 

HPV Public Comments Submitted Via Email

From: sullivan75@comcast.net.

Sent: Sunday, June 12, 2016.8:09 PM 

To: Advisory Committee on Immunization Practices (CDC) 

Subject: June 22 meeting 

This document has been archived for historical purposes. (7/1/2016)
formulas of vaccine, or at least look into and honestly evaluate, perhaps there would not be 

such a distrust. What happened to our system? What happened to doctors’ oath of "Do No 

Harm"? 

I can say this, my daughters were straight A honor students, AP and IB classes, recruited 

athletes, and then became chronically ill after the first Gardasil injection. Because I did not 

know symptoms were because of vaccine my oldest daughter got the second shot at same time 

my second daughter got first shot. My daughter became increasingly ill. I have been in over 20 

ambulance rides in the last 10 months. I deal with their lines on a daily basis. My kids have 

been dismissed by many as having a psychological cause for the symptoms. However, 

because of my connections at hospitals in NY, we got to the bottom of their issues: Autonomic 

dysfunction, histamine intolerance, and high levels of circulating levels of epinephrine, 

norepinephrine, renin, and vasopressin. My once brilliant loving daughter cannot even have 

empathy for others as her affect completely changed within five days of vaccine. 

Please hear the cry of these parents. I personally talk on a daily basis with 800 other moms 

whose children have been affected in the exact same way. I am out over 20,000 in doctor bills. 

It is unfair that I had to seek and seek and seek just for someone to listen. And I am the lucky 

one. Please look into the study done by Dr. Sin Hang Lee. I know you are aware of his letter to 

the WHO, but his science is good and it is what happened to our children.

God is watching and weather you believe or not, on Judgement day all who knew something 

was ignored and did it anyway will pay. My children have lost so much and not sure they will 

ever get it back. There are ways to help these kids. Take responsibility get this vaccine off the 

market and demand doctors find ways to help. I am begging. 

Sincerely a grieving Mother 

Deborah Sullivan

No public comments were offered during this session.

Day 2: Public Comment

This document has been archived for historical purposes. (7/1/2016)
 

Upon reviewing the foregoing version of the June 22-23, 2016 ACIP meeting minutes, Dr. 

Nancy Bennett, ACIP Chair, certified that to the best of her knowledge, they are accurate and 

complete. Her original, signed certification is on file with the Management Analysis and 

Services Office (MASO) of CDC.

Certification

This document has been archived for historical purposes. (7/1/2016)
February 18, 2016

Department of Health and Human Services

Centers for Disease Control and Prevention

Advisory Committee on Immunization Practices

July 1, 2015 – June 30, 2016

CHAIR

BENNETT, Nancy, MD, MS

Professor of Medicine and Public Health Sciences

Director, Center for Community Health

Co-director, Clinical and Translational Science Institute

University of Rochester School of Medicine and Dentistry

Rochester, NY 

Term: 07/01/2015-06/30/2018

EXECUTIVE SECRETARY

COHN, Amanda, MD

Senior Advisor for Vaccines 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Atlanta, GA

MEMBERS

BELONGIA, Edward, MD

Director 

Center for Clinical Epidemiology & Population Health 

Marshfield Clinic Research Foundation

Marshfield, WI

Term: 07/01/2014-06/30/2018

EZEANOLUE, Echezona, MD, MPH 

Professor of Pediatrics and Public Health

Department of Epidemiology and Biostatistics

Director, Global Health and Implementation Research Initiatives

University of Nevada

Las Vegas, NV

Term: 07/01/2015-06/30/2019

HARRIMAN, Kathleen, PhD, MPH, RN

Chief, Vaccine Preventable Disease Epidemiology Section

Immunization Branch

California Department of Public Health

Richmond, CA

Term: 07/01/2012 – 06/30/2016

ACIP Membership Roster

This document has been archived for historical purposes. (7/1/2016)
HARRISON, Lee H., MD 

Professor of Medicine and Epidemiology

Infectious Diseases Epidemiology Research Unit 

University of Pittsburgh

Pittsburgh, PA

Term: 07/01/2012 – 06/30/2016

KARRON, Ruth A., MD

Professor and Director

Center for Immunization Research 

Department of International Health

Johns Hopkins Bloomberg School of Public Health 

Baltimore, MD

Term: 07/01/2012 – 06/30/2016

KEMPE, Allison, MD, MPH

Professor of Pediatrics

Director of Primary Care Fellowship

University of Colorado School of Medicine

Director of Research

Division of General Academic Pediatrics

Director of Children’s Outcomes Research Program

The Children’s Hospital of Denver

Denver, CO

Term: 07/01/2013 - 06/30/2017

MOORE, Kelly, MD, MPH,

Director, Tennessee Immunization Program 

Tennessee Department of Health 

Assistant Clinical Professor, Department of Health Policy 

Vanderbilt University School of Medicine 

Nashville, TN

Term: 07/01/2015-06/30/2019

PELLEGRINI, Cynthia

Senior Vice President

Public Policy and Government Affairs

March of Dimes

Washington, DC

Term: 07/01/2013-06/30/2017

REINGOLD, Arthur L., MD

Professor of Epidemiology

Edward Penhoet Distinguished for Global Health and Infectious Disease

Associate Dean for Research

School of Public Health

University of California

Berkeley, CA

Term: 07/01/2013-06/30/2017

This document has been archived for historical purposes. (7/1/2016)
RILEY, Laura E., MD

Associate Professor, Obstetrics, Gynecology and Reproductive Medicine 

Harvard Medical School 

Maternal Fetal Medicine 

Massachusetts General Hospital

Boston, MA

Term: 07/01/2014-06/30/2018

ROMERO, José R., MD, FAAP

Professor of Pediatrics

Horace C. Cabe Endowed Chair in Infectious Diseases

Director, Pediatric Infectious Diseases Section

University of Arkansas for Medical Sciences and Arkansas Children's Hospital 

Director, Clinical Trials Research

Arkansas Children's Hospital Research Institute

Little Rock, AR

Term: 07/01/2014-06/30/2018

RUBIN, Lorry, MD

Director 

Pediatric Infectious Diseases

Steven and Alexandra Cohen Children’s Medical Center of New York

North Shore-Long Island Jewish Health System

New Hyde Park, NY

Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine

Hempstead, NY

Term: 07/01/2012 – 06/30/2016

STEPHENS, David, MD 

Professor of Medicine, Division of Infectious Diseases 

Chair, Department of Medicine 

Emory University School of Medicine 

Emory University 

Atlanta, GA 

Term: 07/01/2015-06/30/2019

WALTER, Emmanuel (Chip), Jr., MD, MPH

Professor of Pediatrics

Duke University School of Medicine

Durham, NC

Term: 07/01/2015-06/30/2019

This document has been archived for historical purposes. (7/1/2016)
EX OFFICIO MEMBERS

Centers for Medicare and Medicaid Services (CMS)

HANCE, Mary Beth

Senior Policy Advisor

Division of Quality, Evaluations and Health Outcomes

Children and Adults Health Programs Group

Center for Medicaid, CHIP and Survey & Certification

Centers for Medicare and Medicaid Services

Baltimore, MD

Department of Defense (DoD)

SERGIENKO, Eric, MD, MPH

CAPT, Medical Corps, United States Navy

Department of Defense Liaison

Centers for Disease Control and Prevention

Atlanta, GA

Department of Veterans Affairs (DVA)

KIM, Jane A., MD, MPH

Deputy Chief Consultant for Preventive Medicine

Office of Patient Care Services

National Center for Health Promotion and Disease Prevention

Durham, North Carolina 

Food and Drug Administration (FDA) 

SUN, Wellington, MD

Director, Division of Vaccines and Related Product Applications

Office of Vaccines Research and Review

Food and Drug Administration

Rockville, MD 

Health Resources and Services Administration (HRSA)

NAIR, Narayan, MD

CAPT, USPHS

Acting Division Director/Chief Medical Officer

Division of Injury Compensation Programs

Healthcare Systems Bureau

Rockville, MD

Indian Health Service (IHS)

GROOM, Amy, MPH

Immunization Program Manager

Indian Health Service

Albuquerque, NM

This document has been archived for historical purposes. (7/1/2016)
National Vaccine Program Office (NVPO)

GELLIN, Bruce, MD, MPH

Director

National Vaccine Program Office

Department of HHS, Public Health and Science

Washington, DC

National Institutes of Health (NIH)

GORMAN, Richard L., MD

Associate Director for Clinical Research

Division of Microbiology and Infectious Diseases/NIAID

National Institute of Health

Bethesda, MD

LIAISON REPRESENTATIVES

American Academy of Family Physicians (AAFP)

SAVOY, Margot, MD, MPH 

Medical Director, Department of Family & Community Medicine

Christiana Care Health System

Wilmington, DE

American Academy of Pediatrics (AAP)

BYINGTON, Carrie L., MD

Chair, AAP Committee on Infectious Diseases

H.A. and Edna Benning Presidential Professor of Pediatrics

Associate Vice President for Faculty and Academic Affairs

University of Utah Health Sciences Center

Salt Lake City, UT

American Academy of Pediatrics (AAP)

Red Book Editor 

KIMBERLIN, David, MD

Professor of Pediatrics

Division of Pediatric Infectious Diseases

The University of Alabama at Birmingham School of Medicine

Birmingham, AL

American Academy of Physician Assistants (AAPA)

LÉGER, Marie-Michèle, MPH, PA-C 

Senior Director, Clinical and Health Affairs

American Academy of Physician Assistants

Alexandria, VA

American College Health Association (ACHA)

EVEN, Susan, MD

Executive Director

Student Health Center

University of Missouri

Columbia, MO

This document has been archived for historical purposes. (7/1/2016)
Advisory Committee on Immunization Practices (ACIP) Summary Report June 22-23, 2016

American College of Nurse Midwives (ACNM)

HAYES, Carol E., CNM, MN, MPH

Atlanta Perinatal Associates

Atlanta, GA

American College of Nurse Midwives (ACNM) (alternate)

MEHARRY, Pamela M., PHD, CNM

Midwifery Educator, Human Resources for Health 

In partnership with University of Rwanda and University of Illinois, Chicago

American College of Obstetricians and Gynecologists (ACOG)

AULT, Kevin A., MD, FACOG

Professor and Division Director

Department of Obstetrics and Gynecology

University of Kansas Medical Center 

Kansas City, KS

American College of Physicians (ACP)

FRYHOFER, Sandra Adamson., MD, MACP

Adjunct Associate Professor of Medicine

Emory University School of Medicine

Atlanta, GA

American College of Physicians (ACP) (alternate)

POLAND, Gregory A., MD

Mary Lowell Professor of Medicine and Infectious Diseases

Mayo Clinic 

Rochester, MN

American Geriatrics Society (AGS)

SCHMADER, Kenneth, MD

Professor of Medicine-Geriatrics

Geriatrics Division Chief

Duke University and Durham VA Medical Centers

Durham, NC

America’s Health Insurance Plans (AHIP)

NETOSKIE, Mark J., MD, MBA

Market Medical Executive, CIGNA 

Houston, TX

American Medical Association (AMA)

FRYHOFER, Sandra Adamson., MD

Adjunct Associate Professor of Medicine

Emory University School of Medicine

Atlanta, GA

This document has been archived for historical purposes. (7/1/2016)
American Nurses Association (ANA)

RITTLE, Charles (Chad), DNP, MPH, RN

Assistant Professor, Nursing Faculty

Chatham University, School of Health Sciences

Pittsburgh, PA

American Osteopathic Association (AOA)

GROGG, Stanley E., DO

Associate Dean/Professor of Pediatrics

Oklahoma State University-Center for Health Sciences

Tulsa, OK

American Pharmacists Association (APhA)

FOSTER, Stephan L., PharmD

Professor and Vice Chair, Department of Clinical Pharmacy

University of Tennessee Health Sciences Center, College of Pharmacy

Memphis, TN

Association of Immunization Managers (AIM)

FINLEY, Christine, RN, MPH 

Immunization Program Manager 

Vermont Department of Health

Burlington, VT

Association for Prevention Teaching and Research (APTR)

McKINNEY, W. Paul, MD

Professor and Associate Dean

University of Louisville School of Public Health and Information Sciences

Louisville, KY

Association of State and Territorial Health Officials (ASTHO)

DWELLE, Terry L, MD, MPHTM

State Health Officer

North Dakota Department of Health

Bismarck, ND

Biotechnology Industry Organization (BIO)

ARTHUR, Phyllis A., MBA

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy

Washington, DC 

Council of State and Territorial Epidemiologists (CSTE) 

HAHN, Christine, MD

State Epidemiologist

Office of Epidemiology, Food Protection and Immunization

Idaho Department of Health and Welfare

Boise, ID

This document has been archived for historical purposes. (7/1/2016)
160 

Canadian National Advisory Committee on Immunization (NACI)

GEMMILL, Ian MacDonald, MD

Medical Officer of Health 

Kingston, Frontenac and Lennox & Addington Public Health 

Kingston, Ontario, Canada

Infectious Diseases Society of America (IDSA)

NEUZIL, Kathleen M., MD, MPH

Professor of Medicine

Director, Center for Vaccine Development

University of Maryland School of Medicine

Baltimore, MD

Infectious Diseases Society of America (IDSA) (alternate)

BAKER, Carol J., MD

Professor of Pediatrics

Molecular Virology and Microbiology

Baylor College of Medicine

Houston, TX

National Association of County and City Health Officials (NACCHO)

ZAHN, Matthew, MD

Medical Director, Epidemiology

Orange County Health Care Agency

Santa Ana, CA

National Association of County and City Health Officials (NACCHO) (alternate)

DUCHIN, Jeffrey, MD

Health Officer and Chief, Communicable Disease Epidemiology and Immunization Section 

Public Health - Seattle and King County

Professor in Medicine 

Division of Allergy and Infectious Diseases

University of Washington School of Medicine and School of Public Health

Seattle, WA

National Association of Pediatric Nurse Practitioners (NAPNAP)

STINCHFIELD, Patricia A., RN, MS, CPNP

Director

Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota

St. Paul, MN

National Foundation for Infectious Diseases (NFID)

SCHAFFNER, William, MD

Chairman, Department of Preventive Medicine

Vanderbilt University School of Medicine

Nashville, TN

This document has been archived for historical purposes. (7/1/2016)
Advisory Committee on Immunization Practices (ACIP) Summary Report June 22-23, 2016

National Immunization Council and Child Health Program, Mexico

VILLASEÑOR RUIZ, Ignacio, MD 

Directora del Programa de Atencion da la Salud de la Infancia y la Adolescencia / Director 

General, Child and Adolescent Health

Centro Nacional Para la Salud de la Infancia Y La Adolescencia / National Center for Child and 

Adolescent Health

Ministry of Health / Secretaría de Salud

Mexico

National Medical Association (NMA)

WHITLEY-WILLIAMS, Patricia, MD

Professor and Chair

University of Medicine and Dentistry of New Jersey

Robert Wood Johnson Medical School 

New Brunswick, NJ

National Vaccine Advisory Committee (NVAC)

ORENSTEIN, Walt, MD

Chair, NVAC 

Associate Director, Emory Vaccine Center

Emory University

Atlanta, GA

Pediatric Infectious Diseases Society (PIDS)

O’LEARY, Sean, MD, MPH

Associate Professor of Pediatrics

Pediatric Infectious Diseases

General Academic Pediatrics

Children’s Hospital Colorado

University of Colorado School of Medicine

Pediatric Infectious Diseases Society (PIDS) (alternate)

SAWYER, Mark H, MD

Professor of Clinical Pediatrics

University of California, San Diego School of Medicine

San Diego, CA

Pharmaceutical Research and Manufacturers of America (PhRMA)

JOHNSON, David R, MD, MPH 

Associate Vice President, Global Medical Affairs, Sanofi Pasteur 

Swiftwater, PA

Society for Adolescent Health and Medicine (SAHM)

MIDDLEMAN, Amy B., MD, MSEd, MPH

Professor of Pediatrics

Chief, Section of Adolescent Medicine

University of Oklahoma Health Sciences Center

Oklahoma City, OK

This document has been archived for historical purposes. (7/1/2016)
Society for Healthcare Epidemiology of America (SHEA)

WEBER, David, MD, MPH

Professor of Medicine, Pediatrics, and Epidemiology

University of North Carolina Schools of Medicine and Public Health

Medical Director, Hospital Epidemiology and Occupational Health, UNC Health Care

University of North Carolina

Chapel Hill, NC

This document has been archived for historical purposes. (7/1/2016)